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    Clinical Trial Results:
    An open-label, multi-center, expanded access study of pasireotide s.c. in patients with Cushing’s disease

    Summary
    EudraCT number
    		 2010-024165-44
    Trial protocol
    		 DE   GR   ES   CZ   NL  
    Global end of trial date
    26 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Feb 2018
    First version publication date
    11 Feb 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CSOM230B2406
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01582061
    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
    26 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to document the safety of pasireotide subucanteous in patients with Cushing's disease
    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
    16 Aug 2011
    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
    Germany: 15
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United States: 26
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Brazil: 17
    Country: Number of subjects enrolled
    Thailand: 8
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Lebanon: 3
    Country: Number of subjects enrolled
    Russian Federation: 2
    Worldwide total number of subjects
    104
    EEA total number of subjects
    36
    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)
    99
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 After a 21-day screening period, patients who met the inclusion/exclusion criteria received pasireotide subcutaneous twice a day (BID)

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pasireotide 600 μg
    Arm description
    		 Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pasireotide
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Starting dose was 600 μg bid for all patients in the European Union (EU) and all other countries starting dose was 900 μg bid, however, for patients with impaired glucose metabolism 600 μg bid was the starting dose.

    Arm title
    		 Pasireotide 900 μg
    Arm description
    		 Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pasireotide
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Starting dose was 600 μg bid for all patients in the European Union (EU) and all other countries starting dose was 900 μg bid, however, for patients with impaired glucose metabolism 600 μg bid was the starting dose.

    Number of subjects in period 1
    		Pasireotide 600 μg Pasireotide 900 μg
    Started
    49
    55
    Completed
    21
    19
    Not completed
    28
    36
         Abnormal laboratory value(s)
    1
    -
         condition no longer requires study drug
    1
    -
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    10
    4
         Adverse event, non-fatal
    12
    8
         Lost to follow-up
    1
    -
         Lack of efficacy
    3
    23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pasireotide 600 μg
    Reporting group description
    		 Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.

    Reporting group title
    Pasireotide 900 μg
    Reporting group description
    		 Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day

    Reporting group values
    		 Pasireotide 600 μg Pasireotide 900 μg Total
    Number of subjects
    		 49 55 104
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 46 53 99
        From 65-84 years
    		 3 2 5
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.5 ( 13.14 ) 39.9 ( 12.55 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 37 47 84
        Male
    		 12 8 20
    Race (NIH/OMB)
    Units: Subjects
        Asian
    		 6 15 21
        Black or African American
    		 3 2 5
        White
    		 39 36 75
        Unknown or Not Reported
    		 1 2 3

    End points

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    End points reporting groups
    Reporting group title
    Pasireotide 600 μg
    Reporting group description
    		 Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.

    Reporting group title
    Pasireotide 900 μg
    Reporting group description
    		 Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day

    Subject analysis set title
    600 µg bid - all grades
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All grades of adverse events. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose < 1500 μg /day.

    Subject analysis set title
    600 μg - grades 3/4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Adverse event grades 3 and 4. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients

    Subject analysis set title
    900 μg - all grades
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All grades of adverse events. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day

    Subject analysis set title
    900 μg - grades 3/4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Adverse event grades 3 and 4. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg

    Subject analysis set title
    All patients - all grades
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All grades of adverse events for all patients who received 600 µg bid or 900 µg bid of pasireotide sub-cutaneous.

    Subject analysis set title
    All patients - grades 3/4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Grades 3 and 4 of adverse events for all patients who received 600 µg bid or 900 µg bid of pasireotide sub-cutaneous.

    Subject analysis set title
    All patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients received pasireotide 600 μg or 900 μg BID

    Subject analysis set title
    All patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients received pasireotide 600 μg or 900 μg BID

    Subject analysis set title
    All patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients received pasireotide 600 μg or 900 μg BID

    Primary: Percentage of patients with a drug-related adverse event that is recorded as grade 3 or 4 or as a serious adverse event (SAE)

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    End point title
    		 Percentage of patients with a drug-related adverse event that is recorded as grade 3 or 4 or as a serious adverse event (SAE) [1]
    End point description
    Only AEs occurring on or after the start of study treatment and no more than 28 days after the discontinuation of study treatment. A patient with multiple occurrences of an AE under one treatment is counted only once in the AE category for that treatment. A patient with multiple severity grades for an AE while on a treatment, is only counted under the maximum grade.
    End point type
    Primary
    End point timeframe
    Baseline up to approximately 256 weeks
    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 done.
    End point values
    		 600 µg bid - all grades 600 μg - grades 3/4 900 μg - all grades 900 μg - grades 3/4 All patients - all grades All patients - grades 3/4
    Number of subjects analysed
    49
    26
    55
    15
    104
    41
    Units: percentage of participants
    number (not applicable)
        Any primary system organ class|
    53.1
    53.1
    29.1
    27.3
    40.4
    39.4
        Metabolism and nutrition disorders|
    26.5
    26.5
    12.7
    10.9
    19.2
    18.3
        Gastrointestinal disorders|
    18.4
    18.4
    7.3
    7.3
    12.5
    12.5
        Investigations|
    8.2
    8.2
    3.6
    3.6
    5.8
    5.8
        Hepatobiliary disorders|
    2.0
    2.0
    5.5
    5.5
    3.8
    3.8
        Endocrine disorders|
    6.1
    6.1
    0
    0
    2.9
    2.9
        Gen disorders,admin site conditions|
    4.1
    4.1
    0
    0
    1.9
    1.9
        Ear and labyrinth disorders|
    2.0
    2.0
    0
    0
    1.0
    1.0
        Infections and infestations|
    2.0
    2.0
    0
    0
    1.0
    1.0
        Musculoskeletal and connective tissue disorders|
    2.0
    2.0
    0
    0
    1.0
    1.0
        Neoplasms benign, malignant and unspecified|
    2.0
    2.0
    0
    0
    1.0
    1.0
        Nervous system disorders|
    2.0
    2.0
    0
    0
    1.0
    1.0
        Psychiatric disorders|
    0
    0
    1.8
    1.8
    1.0
    1.0
        Respiratory, thoracic, mediastinal disorders|
    0
    0
    1.8
    0
    1.0
    0
    No statistical analyses for this end point

    Secondary: Percentage of patients with mean Urinary Free Cortisol (UFC) ≤ Upper Limit of Normal (ULN)

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    End point title
    		 Percentage of patients with mean Urinary Free Cortisol (UFC) ≤ Upper Limit of Normal (ULN)
    End point description
    The 24h-UFC concentration results from three samples during screening were averaged to obtain baseline. After baseline, mean 24h UFC was determined at week 24. At Week 4, 8, 16 and 20, mean 24h UFC was determined from two 24 hour urine collections collected on two consecutive days occurring before the visit. At Week 12, 24 and 48, the mean 24h-UFC from three 24 hour urine collections, collected over the week before the visit, was determined. After Week 24, the mean 24h UFC was determined at 12–week intervals until end of study visit, from two 24 hour collections during two consecutive days prior to each respective visit (except at Week 48). UFC was determined by liquid chromatography tandem mass spectroscopy (LC/MS/MS). The normal ranges were determined by the central laboratory’s own reference range. All samples, including screening samples, were analyzed by a central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    49
    55
    104
    Units: percentage of participants
    number (confidence interval 95%)
        Week 12|
    77.8 (57.74 to 91.38)
    38.5 (23.36 to 55.38)
    54.5 (41.81 to 66.86)
        Week 24|
    68.2 (45.13 to 86.14)
    29.2 (12.62 to 51.09)
    47.8 (32.89 to 63.05)
        Week 48|
    70.0 (34.75 to 93.33)
    18.2 (2.28 to 51.78)
    42.9 (21.82 to 65.98)
        Week 24 (LOCF)|
    54.1 (36.92 to 70.51)
    28.6 (16.59 to 43.26)
    39.5 (29.15 to 50.66)
        Week 48 (LOCF)|
    51.4 (34.40 to 68.08)
    22.4 (11.78 to 36.62)
    34.9 (24.92 to 45.92)
    No statistical analyses for this end point

    Secondary: Percentage of patients achieving a reduction of mean UFC ≥ 50% from baseline

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    End point title
    		 Percentage of patients achieving a reduction of mean UFC ≥ 50% from baseline
    End point description
    The 24h-UFC concentration results from three samples during screening were averaged to obtain baseline. After baseline, mean 24h UFC was determined at week 24. At Week 4, 8, 16 and 20, mean 24h UFC was determined from two 24 hour urine collections collected on two consecutive days occurring before the visit. At Week 12, 24 and 48, the mean 24h-UFC from three 24 hour urine collections, collected over the week before the visit, was determined. After Week 24, the mean 24h UFC was determined at 12–week intervals until end of study visit, from two 24 hour collections during two consecutive days prior to each respective visit (except at Week 48). UFC was determined by liquid chromatography tandem mass spectroscopy (LC/MS/MS). The normal ranges were determined by the central laboratory’s own reference range. All samples, including screening samples, were analyzed by a central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    49
    55
    104
    Units: percentage of participants
    number (confidence interval 95%)
        Week 12|
    74.1 (53.72 to 88.89)
    48.7 (32.42 to 65.22)
    59.1 (46.29 to 71.05)
        Week 24|
    68.2 (45.13 to 86.14)
    29.2 (12.62 to 51.09)
    47.8 (32.89 to 63.05)
        Week 48|
    70.0 (34.75 to 93.33)
    18.2 (2.28 to 51.78)
    42.9 (21.82 to 65.98)
        Week 24 (LOCF)|
    56.8 (39.49 to 72.90)
    38.8 (25.20 to 53.76)
    46.5 (35.68 to 57.59)
        Week 48 (LOCF)|
    51.4 (34.40 to 68.08)
    42.9 (28.82 to 57.79)
    46.5 (35.68 to 57.59)
    No statistical analyses for this end point

    Secondary: Percent change in Cushing Quality of Life and Work Productivity and Activity Impairment-General Health (WPAI-GH) scores

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    End point title
    		 Percent change in Cushing Quality of Life and Work Productivity and Activity Impairment-General Health (WPAI-GH) scores
    End point description
    A 12-item Cushing’s syndrome HRQoL questionnaire (CushingQoL, cf. Webb et al 2008) was implemented and patients who completed 9 or more items at a visit were considered evaluable for that visit. The standardized scores were calculated as follows: 1) Obtain raw scores, denoted by X, as the sum of all the ratings on all the HRQoL questions for a single patient and the score can range from 12 (worst HRQoL) to 60 points (best HRQoL). Therefore, the lower the score, greater the negative impact on HRQoL and 2) obtain standardized score, Y, for a single patient • Y = 100 (X-12) / (60-12) = 100 (X-12)/48. For example, if a patient answers all 12 items with ‘Sometimes’ or ‘Somewhat’, X = 36 and Y = 100 ∙ 24/48 = 50 The WPAI-GH questionnaire was used to assess work productivity and activity impairment. However, there was very limited baseline data and therefore the results and outcomes of the objective, ‘change from baseline in WPAI-GH scores’ are not included.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    47
    54
    104
    Units: percent change in score
    arithmetic mean (standard deviation)
        Week 12|
    21.3 ( 47.03 )
    100.8 ( 252.25 )
    67.1 ( 197.09 )
        Week 24|
    36.7 ( 59.25 )
    119.7 ( 321.61 )
    82.3 ( 243.19 )
        Week 48|
    24.0 ( 37.76 )
    42.3 ( 60.75 )
    34.4 ( 52.29 )
    No statistical analyses for this end point

    Secondary: Percent change in Cushing’s disease clinical signs and symptoms - blood pressure (BP)

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    End point title
    		 Percent change in Cushing’s disease clinical signs and symptoms - blood pressure (BP)
    End point description
    Standing systolic and diastolic BP based on 1 assessment and sitting systolic and diastolic BP was mean of 3 assessments.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    49
    55
    104
    Units: percent change of mmhg
    arithmetic mean (standard deviation)
        Sitting systolic Week 12|
    -6.8 ( 12.04 )
    -1.4 ( 14.40 )
    -3.8 ( 13.61 )
        Sitting systolic Week 24|
    -7.4 ( 8.97 )
    -5.7 ( 11.09 )
    -6.5 ( 10.13 )
        Sitting systolic Week 48|
    -5.1 ( 8.57 )
    -4.7 ( 12.55 )
    -4.9 ( 10.87 )
        Standing systolic Week 12|
    -7.9 ( 12.49 )
    -3.6 ( 15.38 )
    -5.5 ( 14.27 )
        Standing systolic Week 24|
    -10.9 ( 10.30 )
    -6.7 ( 14.09 )
    -8.6 ( 12.62 )
        Standing systolic Week 48|
    -6.5 ( 9.45 )
    -4.4 ( 13.86 )
    -5.3 ( 12.10 )
        Sitting diastolic Week 12|
    -4.6 ( 15.13 )
    -0.2 ( 14.40 )
    -2.1 ( 14.79 )
        Sitting diastolic Week 24|
    -6.2 ( 7.29 )
    -3.8 ( 15.83 )
    -4.9 ( 12.65 )
        Sitting diastolic Week 48|
    -3.3 ( 10.38 )
    -4.3 ( 13.93 )
    -3.8 ( 12.37 )
        Standing diastolic Week 12|
    -5.5 ( 16.02 )
    -1.9 ( 17.63 )
    -3.5 ( 16.93 )
        Standing diastolic Week 24|
    -7.6 ( 10.30 )
    -5.3 ( 16.74 )
    -6.3 ( 14.18 )
        Standing diastolic Week 48|
    -2.1 ( 13.78 )
    -4.4 ( 14.13 )
    -3.4 ( 13.83 )
    No statistical analyses for this end point

    Secondary: Percent change in Cushing’s disease clinical signs and symptoms - pulse

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    End point title
    		 Percent change in Cushing’s disease clinical signs and symptoms - pulse
    End point description
    Change from baseline is shown as: Percent change from baseline (BL) =((Post BL value – BL value)/ BL value)*100
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    49
    55
    104
    Units: percent change in bpm
    arithmetic mean (standard deviation)
        Sitting pulse Week 12|
    2.3 ( 18.93 )
    -7.5 ( 11.50 )
    -3.2 ( 15.87 )
        Sitting pulse Week 24|
    -1.8 ( 17.05 )
    -2.6 ( 18.07 )
    -2.2 ( 17.46 )
        Sitting pulse Week 48|
    2.9 ( 16.39 )
    3.7 ( 15.46 )
    3.3 ( 15.65 )
    No statistical analyses for this end point

    Secondary: Percent change in Cushing’s disease clinical signs and symptoms - Temperature

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    End point title
    		 Percent change in Cushing’s disease clinical signs and symptoms - Temperature
    End point description
    Body temperature in celsius
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    49
    55
    104
    Units: percent change of degrees celius
    arithmetic mean (standard deviation)
        Week 12|
    0.1 ( 1.26 )
    -0.3 ( 1.06 )
    -0.1 ( 1.17 )
        Week 24|
    -0.1 ( 1.15 )
    -0.1 ( 1.26 )
    -0.1 ( 1.20 )
        Week 48|
    0.03 ( 1.47 )
    -0.1 ( 1.19 )
    0.1 ( 1.31 )
    No statistical analyses for this end point

    Secondary: Percent change in Cushing’s disease clinical signs and symptoms - Body mass index (BMI)

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    End point title
    		 Percent change in Cushing’s disease clinical signs and symptoms - Body mass index (BMI)
    End point description
    Percent of patients reducing by at least one class level. Class levels: <25.0, 25.0 to <30.0, ≥ 30.0
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    49
    55
    104
    Units: percent change in kg/m2
    arithmetic mean (standard deviation)
        Week 12|
    -4.2 ( 3.70 )
    -4.8 ( 5.38 )
    -4.5 ( 4.69 )
        Week 24|
    -7.3 ( 5.46 )
    -5.2 ( 6.51 )
    -6.1 ( 6.10 )
        Week 48|
    -8.0 ( 6.82 )
    -6.3 ( 7.88 )
    -7.0 ( 7.39 )
    No statistical analyses for this end point

    Secondary: Percent change in Cushing’s disease clinical signs and symptoms - Weight

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    End point title
    		 Percent change in Cushing’s disease clinical signs and symptoms - Weight
    End point description
    Clinically relevant threshold (at any time point) was reduction of ≥ 5%
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    49
    55
    104
    Units: percent change in kg
    arithmetic mean (standard deviation)
        Week 12|
    -4.2 ( 3.70 )
    -4.8 ( 5.38 )
    -4.5 ( 4.69 )
        Week 24|
    -7.3 ( 5.46 )
    -5.2 ( 6.51 )
    -6.1 ( 6.10 )
        Week 48|
    -8.0 ( 6.82 )
    -6.3 ( 7.88 )
    -7.0 ( 7.39 )
    No statistical analyses for this end point

    Secondary: Percent change in Cushing’s disease clinical signs and symptoms - Muscle Strength

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    End point title
    		 Percent change in Cushing’s disease clinical signs and symptoms - Muscle Strength
    End point description
    Direct observation of ability to stand unaided: 0=able to stand easily with arms extended, 1=able to stand after several efforts without using arms as assistance, 2=able to stand only by using arms as assistance 3=completely unable to stand
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    49
    55
    104
    Units: percent change in scores
    arithmetic mean (standard deviation)
        Week 12|
    -34.6 ( 62.53 )
    -53.7 ( 46.98 )
    -42.4 ( 56.28 )
        Week 24|
    -28.6 ( 48.80 )
    -47.6 ( 50.40 )
    -38.1 ( 48.67 )
        Week 48|
    -30.0 ( 44.72 )
    -75.0 ( 50.0 )
    -50.0 ( 50.00 )
    No statistical analyses for this end point

    Secondary: Percent change in Cushing’s disease clinical signs and symptoms - Waist circumference

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    End point title
    		 Percent change in Cushing’s disease clinical signs and symptoms - Waist circumference
    End point description
    Clinically relevant threshold (at any time point). Reduction of ≥ 5%, Reduction of ≥ 10%
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    49
    55
    104
    Units: percent change of centimeters
    arithmetic mean (standard deviation)
        Week 12|
    -2.0 ( 4.29 )
    -2.9 ( 6.70 )
    -2.5 ( 5.72 )
        Week 24|
    -5.8 ( 6.28 )
    -3.1 ( 5.48 )
    -4.4 ( 5.96 )
        Week 48|
    -5.1 ( 5.74 )
    -4.1 ( 5.64 )
    -4.6 ( 5.62 )
    No statistical analyses for this end point

    Secondary: Percent change in Cushing’s disease clinical signs and symptoms - Hirsutism

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    End point title
    		 Percent change in Cushing’s disease clinical signs and symptoms - Hirsutism
    End point description
    Change from baseline is shown as: Percent change from baseline (BL) =((Post BL value – BL value)/ BL value)*100. Ferriman-Gallway scoring was used: 0=minimum and 36 was maximum in females only.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    49
    55
    104
    Units: percent change in scores
    arithmetic mean (standard deviation)
        Week 12|
    -12.2 ( 24.57 )
    -8.2 ( 35.30 )
    -10.0 ( 30.00 )
        Week 24|
    -21.2 ( 32.72 )
    -16.2 ( 46.99 )
    18.4 ( 40.79 )
        Week 48|
    -18.2 ( 30.12 )
    9.6 ( 143.83 )
    -2.2 ( 110.20 )
    No statistical analyses for this end point

    Secondary: Percent change from baseline in growth hormone (GH) values

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    End point title
    		 Percent change from baseline in growth hormone (GH) values
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    48
    55
    103
    Units: percent change of µg/L
    arithmetic mean (standard deviation)
        Week 12|
    -17.3 ( 109.89 )
    -20.90 ( 156.60 )
    -19.3 ( 137.33 )
        Week 24|
    -22.2 ( 62.43 )
    -26.2 ( 105.44 )
    -24.4 ( 88.70 )
        Week 48|
    23.1 ( 127.30 )
    -1.0 ( 134.97 )
    9.7 ( 130.32 )
    No statistical analyses for this end point

    Secondary: Percent change from baseline in insulin growth factor - 1 (IGF - 1) values

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    End point title
    		 Percent change from baseline in insulin growth factor - 1 (IGF - 1) values
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, week 12, 24 and 48
    End point values
    		 Pasireotide 600 μg Pasireotide 900 μg All patients
    Number of subjects analysed
    48
    53
    101
    Units: percent change of ng/ml
    arithmetic mean (standard deviation)
        Week 12|
    -53.4 ( 23.66 )
    -57.8 ( 23.93 )
    -55.9 ( 23.76 )
        Week 24|
    -49.2 ( 26.56 )
    -56.2 ( 26.55 )
    -53.1 ( 26.53 )
        Week 48|
    -41.8 ( 35.72 )
    -52.1 ( 21.87 )
    -47.6 ( 28.71 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    600 µg bid
    Reporting group description
    		 600 µg bid

    Reporting group title
    900 µg bid
    Reporting group description
    		 900 µg bid

    Reporting group title
    All patients
    Reporting group description
    		 All patients

    Serious adverse events
    		 600 µg bid 900 µg bid All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 49 (26.53%)
    17 / 55 (30.91%)
    30 / 104 (28.85%)
         number of deaths (all causes)
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pituitary tumour benign
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism venous
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Drug ineffective
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinorrhoea
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood cortisol increased
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase abnormal
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight increased
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         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 disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 49 (4.08%)
    1 / 55 (1.82%)
    3 / 104 (2.88%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 55 (5.45%)
    3 / 104 (2.88%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic lesion
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         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 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glucocorticoid deficiency
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperprolactinaemia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         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
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         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
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    2 / 49 (4.08%)
    1 / 55 (1.82%)
    3 / 104 (2.88%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 49 (4.08%)
    0 / 55 (0.00%)
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 55 (1.82%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 55 (3.64%)
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 55 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 600 µg bid 900 µg bid All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 49 (100.00%)
    54 / 55 (98.18%)
    103 / 104 (99.04%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 49 (6.12%)
    4 / 55 (7.27%)
    7 / 104 (6.73%)
         occurrences all number
    4
    4
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 49 (8.16%)
    7 / 55 (12.73%)
    11 / 104 (10.58%)
         occurrences all number
    4
    8
    12
    Fatigue
         subjects affected / exposed
    11 / 49 (22.45%)
    12 / 55 (21.82%)
    23 / 104 (22.12%)
         occurrences all number
    14
    13
    27
    Injection site erythema
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 55 (3.64%)
    5 / 104 (4.81%)
         occurrences all number
    4
    2
    6
    Oedema peripheral
         subjects affected / exposed
    9 / 49 (18.37%)
    3 / 55 (5.45%)
    12 / 104 (11.54%)
         occurrences all number
    9
    3
    12
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 49 (4.08%)
    3 / 55 (5.45%)
    5 / 104 (4.81%)
         occurrences all number
    6
    4
    10
    Depression
         subjects affected / exposed
    4 / 49 (8.16%)
    3 / 55 (5.45%)
    7 / 104 (6.73%)
         occurrences all number
    4
    3
    7
    Insomnia
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 55 (7.27%)
    5 / 104 (4.81%)
         occurrences all number
    1
    4
    5
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 55 (1.82%)
    4 / 104 (3.85%)
         occurrences all number
    4
    4
    8
    Blood cortisol decreased
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 55 (1.82%)
    4 / 104 (3.85%)
         occurrences all number
    3
    1
    4
    Blood glucose increased
         subjects affected / exposed
    4 / 49 (8.16%)
    9 / 55 (16.36%)
    13 / 104 (12.50%)
         occurrences all number
    6
    10
    16
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 55 (1.82%)
    4 / 104 (3.85%)
         occurrences all number
    4
    1
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 49 (6.12%)
    4 / 55 (7.27%)
    7 / 104 (6.73%)
         occurrences all number
    4
    4
    8
    Insulin-like growth factor decreased
         subjects affected / exposed
    5 / 49 (10.20%)
    5 / 55 (9.09%)
    10 / 104 (9.62%)
         occurrences all number
    8
    5
    13
    Weight decreased
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 55 (3.64%)
    5 / 104 (4.81%)
         occurrences all number
    4
    2
    6
    Injury, poisoning and procedural complications
    Procedural nausea
         subjects affected / exposed
    3 / 49 (6.12%)
    5 / 55 (9.09%)
    8 / 104 (7.69%)
         occurrences all number
    4
    5
    9
    Procedural pain
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 55 (5.45%)
    3 / 104 (2.88%)
         occurrences all number
    0
    3
    3
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    2 / 49 (4.08%)
    3 / 55 (5.45%)
    5 / 104 (4.81%)
         occurrences all number
    5
    4
    9
    Sinus bradycardia
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 55 (1.82%)
    5 / 104 (4.81%)
         occurrences all number
    7
    1
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 49 (12.24%)
    8 / 55 (14.55%)
    14 / 104 (13.46%)
         occurrences all number
    8
    10
    18
    Headache
         subjects affected / exposed
    12 / 49 (24.49%)
    19 / 55 (34.55%)
    31 / 104 (29.81%)
         occurrences all number
    16
    27
    43
    Presyncope
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 55 (1.82%)
    4 / 104 (3.85%)
         occurrences all number
    3
    1
    4
    Syncope
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 55 (0.00%)
    3 / 104 (2.88%)
         occurrences all number
    3
    0
    3
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 55 (5.45%)
    4 / 104 (3.85%)
         occurrences all number
    1
    3
    4
    Abdominal pain
         subjects affected / exposed
    10 / 49 (20.41%)
    9 / 55 (16.36%)
    19 / 104 (18.27%)
         occurrences all number
    11
    10
    21
    Abdominal pain upper
         subjects affected / exposed
    2 / 49 (4.08%)
    6 / 55 (10.91%)
    8 / 104 (7.69%)
         occurrences all number
    3
    6
    9
    Constipation
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 55 (7.27%)
    5 / 104 (4.81%)
         occurrences all number
    1
    4
    5
    Diarrhoea
         subjects affected / exposed
    28 / 49 (57.14%)
    23 / 55 (41.82%)
    51 / 104 (49.04%)
         occurrences all number
    42
    27
    69
    Dry mouth
         subjects affected / exposed
    5 / 49 (10.20%)
    3 / 55 (5.45%)
    8 / 104 (7.69%)
         occurrences all number
    5
    3
    8
    Dyspepsia
         subjects affected / exposed
    2 / 49 (4.08%)
    4 / 55 (7.27%)
    6 / 104 (5.77%)
         occurrences all number
    2
    4
    6
    Faeces soft
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 55 (1.82%)
    5 / 104 (4.81%)
         occurrences all number
    9
    1
    10
    Flatulence
         subjects affected / exposed
    6 / 49 (12.24%)
    5 / 55 (9.09%)
    11 / 104 (10.58%)
         occurrences all number
    6
    5
    11
    Frequent bowel movements
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 55 (3.64%)
    5 / 104 (4.81%)
         occurrences all number
    3
    2
    5
    Nausea
         subjects affected / exposed
    22 / 49 (44.90%)
    26 / 55 (47.27%)
    48 / 104 (46.15%)
         occurrences all number
    29
    36
    65
    Vomiting
         subjects affected / exposed
    3 / 49 (6.12%)
    7 / 55 (12.73%)
    10 / 104 (9.62%)
         occurrences all number
    5
    7
    12
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    8 / 49 (16.33%)
    22 / 55 (40.00%)
    30 / 104 (28.85%)
         occurrences all number
    8
    26
    34
    Hepatic steatosis
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 55 (7.27%)
    5 / 104 (4.81%)
         occurrences all number
    1
    4
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    4 / 49 (8.16%)
    7 / 55 (12.73%)
    11 / 104 (10.58%)
         occurrences all number
    4
    7
    11
    Hyperhidrosis
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 55 (5.45%)
    3 / 104 (2.88%)
         occurrences all number
    0
    3
    3
    Pruritus
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 55 (5.45%)
    4 / 104 (3.85%)
         occurrences all number
    1
    5
    6
    Rash
         subjects affected / exposed
    2 / 49 (4.08%)
    4 / 55 (7.27%)
    6 / 104 (5.77%)
         occurrences all number
    2
    4
    6
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 55 (1.82%)
    5 / 104 (4.81%)
         occurrences all number
    4
    1
    5
    Hypothyroidism
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 55 (1.82%)
    4 / 104 (3.85%)
         occurrences all number
    3
    1
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 49 (4.08%)
    5 / 55 (9.09%)
    7 / 104 (6.73%)
         occurrences all number
    2
    5
    7
    Back pain
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 55 (7.27%)
    5 / 104 (4.81%)
         occurrences all number
    1
    5
    6
    Muscle spasms
         subjects affected / exposed
    2 / 49 (4.08%)
    3 / 55 (5.45%)
    5 / 104 (4.81%)
         occurrences all number
    3
    5
    8
    Myalgia
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 55 (1.82%)
    4 / 104 (3.85%)
         occurrences all number
    3
    1
    4
    Pain in extremity
         subjects affected / exposed
    5 / 49 (10.20%)
    3 / 55 (5.45%)
    8 / 104 (7.69%)
         occurrences all number
    6
    3
    9
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 55 (3.64%)
    5 / 104 (4.81%)
         occurrences all number
    3
    2
    5
    Influenza
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 55 (5.45%)
    4 / 104 (3.85%)
         occurrences all number
    2
    4
    6
    Nasopharyngitis
         subjects affected / exposed
    2 / 49 (4.08%)
    7 / 55 (12.73%)
    9 / 104 (8.65%)
         occurrences all number
    6
    13
    19
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 49 (2.04%)
    6 / 55 (10.91%)
    7 / 104 (6.73%)
         occurrences all number
    1
    8
    9
    Urinary tract infection
         subjects affected / exposed
    0 / 49 (0.00%)
    4 / 55 (7.27%)
    4 / 104 (3.85%)
         occurrences all number
    0
    7
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 49 (12.24%)
    1 / 55 (1.82%)
    7 / 104 (6.73%)
         occurrences all number
    6
    1
    7
    Diabetes mellitus
         subjects affected / exposed
    9 / 49 (18.37%)
    14 / 55 (25.45%)
    23 / 104 (22.12%)
         occurrences all number
    10
    18
    28
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 55 (5.45%)
    4 / 104 (3.85%)
         occurrences all number
    1
    3
    4
    Hyperglycaemia
         subjects affected / exposed
    19 / 49 (38.78%)
    22 / 55 (40.00%)
    41 / 104 (39.42%)
         occurrences all number
    29
    23
    52
    Hypoglycaemia
         subjects affected / exposed
    4 / 49 (8.16%)
    3 / 55 (5.45%)
    7 / 104 (6.73%)
         occurrences all number
    9
    5
    14
    Hypokalaemia
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 55 (5.45%)
    4 / 104 (3.85%)
         occurrences all number
    1
    4
    5
    Type 2 diabetes mellitus
         subjects affected / exposed
    5 / 49 (10.20%)
    3 / 55 (5.45%)
    8 / 104 (7.69%)
         occurrences all number
    5
    3
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Mar 2011
    For better standardization and quality of the laboratory results, a central laboratory for the assessment of all parameters (except urinalysis), was implemented.
    16 Dec 2011
    Additional hepatic-related safety measures were included as a result of an internal hepatic medical review of pasireotide trials
    16 Apr 2012
    Based on the recommendation from the CHMP of the EMA, the starting dose of commercial pasireotide sc was to be 600 μg bid in EU with the option to increase the dose to 900 μg bid if the disease is not controlled (i.e. 24h-mean UFC levels above the ULN) at earliest after two months of treatment provided the 600 μg bid dose is well tolerated by the patient. This change is not applicable for countries outside of the EU. The treatment duration of maximum one year per country has been extended to the latest expected approval date in all participating countries. The treatment duration of maximum one year per country has been extended to the latest expected approval date in all participating countries.
    13 Sep 2013
    Extension of washout period of mifepristone from one to four weeks in inclusion criterion #6. The use of oral contraception after the end of the study was changed to one month (from three months) based on pasireotide sc half-life of proximately 12 hours. As per recently the 2012 ADA and EASD guidelines, further guidelines on hyperglycemia monitoring and management were added. To continue to provide access to countries which have not received pasireotide approval, the protocol has been extended to 31 Dec 2015 from 31 Dec 2013. To be in compliance with the Expanded Access Program requirements, the new process of monthly AE reporting and AESI for pasireotide sc for targeted follow-up were included
    13 Nov 2015
    To continue to provide access to Brazil and South Korea, the protocol was extended to 31 Dec 2016.
    31 Dec 2015
    Monthly reporting of non-serious adverse events was removed from the protocol as it was not required for Expanded Access Programs. It was stated that an interim analysis may be performed per health authority requests or for publication purpose. All reference to medications that might lead to QT prolongation has been re-worded to state “medication with known risk of Torsades de Pointes”.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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