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    Clinical Trial Results:
    Multicenter 3-arm trial to evaluate the efficacy and safety of Pasireotide LAR or Everolimus alone or in combination in patients with well differentiated neuroendocrine carcinoma of the lung and thymus - LUNA Trial

    Summary
    EudraCT number
    		 2011-002872-17
    Trial protocol
    		 GB   IT   SE   ES   FR   NL   DK   DE   GR  
    Global end of trial date
    10 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Feb 2021
    First version publication date
    22 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSOM230DIC03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01563354
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG  
    Sponsor organisation address
    Novartis Campus, 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
    10 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the efficacy of pasireotide long-acting release (LAR) and alone or in combination in progressive patients with a well differentiated neuroendocrine tumorr (NET) of the lung or thymus. The primary endpoint was defined as the proportion of patients who were progression-free at 9 months, according to RECIST version 1.1. The EudraCT system does not accept NA. The EMA work around is that 999 is entered to represent “not available”, “not estimable” or “not evaluable” data.
    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 2013
    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
    Denmark: 5
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Italy: 39
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 20
    Worldwide total number of subjects
    124
    EEA total number of subjects
    104
    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)
    63
    From 65 to 84 years
    61
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Two patients completed the core phase of the study but they did not enter the extension phase one due to worsening in clinical conditions and one for Physician decision.

    Period 1
    Period 1 title
    Core Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pasireotide LAR
    Arm description
    		 Pasireotide long acting release (LAR) 60 mg will be administered as an intra muscular (i.m.) depot injection once every 28 days starting on Day 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pasireotide long-acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Long-acting release 60 mg was administered as an intra muscular depot injection once every 28 days starting at Day 1

    Arm title
    		 Everolimus
    Arm description
    		 Everolimus 10 mg taken orally (p.o) once daily starting on Day 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablets administered orally once a day

    Arm title
    		 Pasireotide LAR and Everolimus Combination
    Arm description
    		 Pasireotide LAR 60 mg i.m. injected once every 28 days + Everolimus 10 mg p.o. daily starting on Day 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pasireotide LAR and Everolimus Combination
    Investigational medicinal product code
    SOM230 + RAD001
    Other name
    Pharmaceutical forms
    Injection, Tablet
    Routes of administration
    Intramuscular use, Oral use
    Dosage and administration details
    Pasireotide LAR 60 mg i.m. injected once every 28 days + Everolimus 10 mg p.o. daily

    Number of subjects in period 1
    		Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Started
    41
    42
    41
    Entered Extension Phase
    12
    14
    15
    Completed
    12
    14
    15
    Not completed
    29
    28
    26
         Adverse event, serious fatal
    1
    5
    2
         Consent withdrawn by subject
    1
    -
    3
         Disease progression
    18
    7
    8
         Adverse event, non-fatal
    5
    15
    13
         Protocol deviation
    2
    -
    -
         PI decision - did not enter extension
    -
    1
    -
         Lost to follow-up
    1
    -
    -
         Clinically got worse-did not enter extension
    1
    -
    -
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pasireotide LAR
    Arm description
    		 Pasireotide long acting release (LAR) 60 mg will be administered as an intra muscular (i.m.) depot injection once every 28 days starting on Day 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pasireotide long-acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Long-acting release 60 mg was administered as an intra muscular depot injection once every 28 days starting at Day 1

    Arm title
    		 Everolimus
    Arm description
    		 Everolimus 10 mg taken orally (p.o) once daily starting on Day 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablets administered orally once a day

    Arm title
    		 Pasireotide LAR and Everolimus Combination
    Arm description
    		 Pasireotide LAR 60 mg i.m. injected once every 28 days + Everolimus 10 mg p.o. daily starting on Day 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pasireotide LAR and Everolimus Combination
    Investigational medicinal product code
    SOM230 + RAD001
    Other name
    Pharmaceutical forms
    Injection, Tablet
    Routes of administration
    Intramuscular use, Oral use
    Dosage and administration details
    Pasireotide LAR 60 mg i.m. injected once every 28 days + Everolimus 10 mg p.o. daily

    Number of subjects in period 2
    		Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Started
    12
    14
    15
    Completed
    0
    0
    0
    Not completed
    12
    14
    15
         Consent withdrawn by subject
    -
    1
    -
         Disease progression
    9
    8
    10
         Administration problems
    3
    2
    3
         Adverse event, non-fatal
    -
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pasireotide LAR
    Reporting group description
    		 Pasireotide long acting release (LAR) 60 mg will be administered as an intra muscular (i.m.) depot injection once every 28 days starting on Day 1

    Reporting group title
    Everolimus
    Reporting group description
    		 Everolimus 10 mg taken orally (p.o) once daily starting on Day 1

    Reporting group title
    Pasireotide LAR and Everolimus Combination
    Reporting group description
    		 Pasireotide LAR 60 mg i.m. injected once every 28 days + Everolimus 10 mg p.o. daily starting on Day 1

    Reporting group values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination Total
    Number of subjects
    		 41 42 41 124
    Age Categorical
    Units: participants
        18 to <65
    		 21 18 24 63
        ≥65 to 84
    		 20 24 17 61
    Sex: Female, Male
    Units:
        Female
    		 15 19 13 47
        Male
    		 26 23 28 77
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 40 42 40 122
        Black
    		 1 0 0 1
        Asian
    		 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Pasireotide LAR
    Reporting group description
    		 Pasireotide long acting release (LAR) 60 mg will be administered as an intra muscular (i.m.) depot injection once every 28 days starting on Day 1

    Reporting group title
    Everolimus
    Reporting group description
    		 Everolimus 10 mg taken orally (p.o) once daily starting on Day 1

    Reporting group title
    Pasireotide LAR and Everolimus Combination
    Reporting group description
    		 Pasireotide LAR 60 mg i.m. injected once every 28 days + Everolimus 10 mg p.o. daily starting on Day 1
    Reporting group title
    Pasireotide LAR
    Reporting group description
    		 Pasireotide long acting release (LAR) 60 mg will be administered as an intra muscular (i.m.) depot injection once every 28 days starting on Day 1

    Reporting group title
    Everolimus
    Reporting group description
    		 Everolimus 10 mg taken orally (p.o) once daily starting on Day 1

    Reporting group title
    Pasireotide LAR and Everolimus Combination
    Reporting group description
    		 Pasireotide LAR 60 mg i.m. injected once every 28 days + Everolimus 10 mg p.o. daily starting on Day 1

    Primary: Percentage of participants progression-free at 9 months based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1)

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    End point title
    		 Percentage of participants progression-free at 9 months based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) [1]
    End point description
    Patients with Complete Response (CR), Partial Response (PR), or Stable Disease (SD) at Month 9 were to be considered as "progression-free” based on RECIST v1.1. Patients with missing tumor assessment, or with overall lesion response “unknown” at Month 9 were considered as “non progression-free”, unless any of the following assessments at Week 48 or Week 52 indicate CR, PR, or SD, in which case the patient was to be considered as progression-free at Month 9. Patients discontinuing the study for any reason prior to the 9 month assessment were to be considered as “non progression-free".
    End point type
    Primary
    End point timeframe
    Baseline up to 9 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No analysis was done
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    41
    42
    41
    Units: percentage of participants
    number (confidence interval 95%)
        Complete response
    0 (0.0 to 8.6)
    0 (0.0 to 8.4)
    0 (0.0 to 8.6)
        Partial response
    2.4 (0.1 to 12.9)
    2.4 (0.1 to 12.6)
    2.4 (0.1 to 12.9)
        Stable disease
    34.1 (20.1 to 50.6)
    31.0 (17.6 to 47.1)
    48.8 (32.9 to 64.9)
        Progression-free (PF) at Month 9
    39.0 (24.2 to 55.5)
    33.3 (19.6 to 49.5)
    58.5 (42.1 to 73.7)
    No statistical analyses for this end point

    Secondary: Summary of progression-free survival (PFS) based on RECIST v1.1

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    End point title
    		 Summary of progression-free survival (PFS) based on RECIST v1.1
    End point description
    Time from first study drug administration to objective tumor progression or death from any cause according to RECIST v1.1
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 69 months
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    41
    42
    41
    Units: months
        median (confidence interval 95%)
    8.51 (5.68 to 14.03)
    12.48 (5.55 to 20.21)
    16.53 (11.10 to 23.26)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier estimates of progression-free survival (PFS)

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    End point title
    		 Kaplan-Meier estimates of progression-free survival (PFS)
    End point description
    Percent (%) event-free probability estimate is the estimated probability that a patient will remain event-free up to the specified time point. Percent event-free probability estimates are obtained from the Kaplan-Meier survival estimates. Events are time from first study drug administration to objective tumor progression or death from any cause according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 69 months
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    41
    42
    41
    Units: event free probability estimates
    number (confidence interval 95%)
        3 months
    83.6 (67.1 to 92.3)
    91.2 (75.1 to 97.1)
    88.6 (72.4 to 95.5)
        6 months
    68.2 (49.8 to 81.1)
    63.5 (44.7 to 77.4)
    85.5 (68.6 to 93.7)
        9 months
    49.6 (31.9 to 65.1)
    56.9 (38.1 to 71.9)
    79.2 (61.1 to 89.5)
        12 months
    39.9 (23.3 to 56.0)
    50.2 (31.9 to 66.0)
    55.5 (36.4 to 71.0)
        15 months
    32.6 (17.2 to 49.1)
    46.8 (28.9 to 62.9)
    51.2 (32.1 to 67.5)
        18 months
    21.8 (9.1 to 37.8)
    38.6 (21.4 to 55.6)
    42.7 (24.2 to 60.1)
        21 months
    14.5 (4.7 to 29.6)
    29.4 (13.6 to 47.2)
    38.0 (20.0 to 55.9)
        24 months
    14.5 (4.7 to 29.6)
    19.6 (6.7 to 37.4)
    28.5 (12.5 to 46.9)
        27 months
    14.5 (4.7 to 29.6)
    19.6 (6.7 to 37.4)
    28.5 (12.5 to 46.9)
        30 months
    10.9 (2.8 to 25.2)
    9.8 (1.8 to 26.2)
    19.0 (6.3 to 36.9)
        33 months
    10.9 (2.8 to 25.2)
    9.8 (1.8 to 26.2)
    19.0 (6.3 to 36.9)
        36 months
    10.9 (2.8 to 25.2)
    9.8 (1.8 to 26.2)
    14.2 (3.7 to 31.5)
        39 months
    10.9 (2.8 to 25.2)
    9.8 (1.8 to 26.2)
    14.2 (3.7 to 31.5)
        42 months
    10.9 (2.8 to 25.2)
    9.8 (1.8 to 26.2)
    14.2 (3.7 to 31.5)
        45 months
    10.9 (2.8 to 25.2)
    9.8 (1.8 to 26.2)
    14.2 (3.7 to 31.5)
        48 months
    10.9 (2.8 to 25.2)
    9.8 (1.8 to 26.2)
    14.2 (3.7 to 31.5)
        51 months
    10.9 (2.8 to 25.2)
    999.9 (999.9 to 999.9)
    14.2 (3.7 to 31.5)
        54 months
    10.9 (2.8 to 25.2)
    999.9 (999.9 to 999.9)
    14.2 (3.7 to 31.5)
        57 months
    10.9 (2.8 to 25.2)
    999.9 (999.9 to 999.9)
    7.1 (0.6 to 25.2)
        60 months
    10.9 (2.8 to 25.2)
    999.9 (999.9 to 999.9)
    7.1 (0.6 to 25.2)
        63 months
    10.9 (2.8 to 25.2)
    999.9 (999.9 to 999.9)
    7.1 (0.6 to 25.2)
        66 months
    999.9 (999.9 to 999.9)
    999.9 (999.9 to 999.9)
    7.1 (0.6 to 25.2)
        69 months
    999.9 (999.9 to 999.9)
    999.9 (999.9 to 999.9)
    7.1 (0.6 to 25.2)
    No statistical analyses for this end point

    Secondary: Number of participants who met criteria for time to response

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    End point title
    		 Number of participants who met criteria for time to response
    End point description
    Time from start of treatment to the first observed objective tumor response (partial response or complete response) observed according to RECIST v1.1. Due to the low number of events, the quartiles were non estimable
    End point type
    Secondary
    End point timeframe
    Every 3 months up to Year 1
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    41
    42
    41
    Units: participants
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Number of participants who met criteria for Duration of Response

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    End point title
    		 Number of participants who met criteria for Duration of Response
    End point description
    Time from onset of the first objective tumor response (partial response or complete response) to objective tumor progression or death from any cause. Due to the low number of events, the duration of response could not be estimated.
    End point type
    Secondary
    End point timeframe
    Every 3 months up to Year 1
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    41
    42
    41
    Units: participants
    1
    1
    1
    No statistical analyses for this end point

    Secondary: 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR)

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    End point title
    		 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR)
    End point description
    Objective response rate (ORR) was defined as the percentage of patients showing a best overall response (BOR) of CR or PR during the core study according to RECIST v1.1 criteria. The best overall response is interpreted as the best response recorded from the start of the treatment until disease progression/recurrence, death from any cause or until the patient withdraws consent, whichever is earliest. DCR was was defined as the percentage of participants with a best overall response of complete response, partial response or stable disease during 12 months of treatment according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 12
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    41
    42
    41
    Units: percentage of participants
    number (confidence interval 95%)
        Objective response (CR+PR)
    2.4 (0.1 to 12.9)
    2.4 (0.1 to 12.6)
    4.9 (0.6 to 16.5)
        Disease control rate (CR+PR+SD)
    80.5 (65.1 to 91.2)
    73.8 (58.0 to 86.1)
    78.0 (62.4 to 89.4)
        Complete response (CR)
    0 (0.0 to 8.6)
    0 (0.0 to 8.4)
    0 (0.0 to 8.6)
        Partial response (PR)
    2.4 (0.1 to 12.9)
    2.4 (0.1 to 12.6)
    4.9 (0.6 to 16.5)
        Stable disease
    78.0 (62.4 to 89.4)
    71.4 (55.4 to 84.3)
    73.2 (57.1 to 85.8)
        Progressive disease
    14.6 (-999.9 to 999.9)
    4.8 (-999.9 to 999.9)
    7.3 (-999.9 to 999.9)
        Unknown
    2.4 (-999.9 to 999.9)
    4.8 (-999.9 to 999.9)
    0 (-999.9 to 999.9)
        Not assessed
    2.4 (-999.9 to 999.9)
    16.7 (-999.9 to 999.9)
    14.6 (-999.9 to 999.9)
        Discontinued before month 12
    68.3 (-999.9 to 999.9)
    64.3 (-999.9 to 999.9)
    63.4 (-999.9 to 999.9)
    No statistical analyses for this end point

    Secondary: Biochemical response rate (BRR) for Chromogranin A (CgA) levels

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    End point title
    		 Biochemical response rate (BRR) for Chromogranin A (CgA) levels
    End point description
    Percentage of patients showing normalization or a decrease of ≥ 30% of serum CgA concentrations compared to baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    34
    27
    35
    Units: percentage of participants
    number (confidence interval 95%)
        Week 12 n=34,27,35
    20.6 (8.7 to 37.9)
    7.4 (0.9 to 24.3)
    17.1 (6.6 to 33.6)
        Week 24 n=34,27,35
    8.8 (1.9 to 23.7)
    7.4 (0.9 to 24.3)
    20.0 (8.4 to 36.9)
        Week 36 n=34,27,35
    8.8 (1.9 to 23.7)
    3.7 (0.1 to 19.0)
    11.4 (3.2 to 26.7)
        Week 48 n=34,27,35
    8.8 (1.9 to 23.7)
    0 (0.0 to 12.8)
    11.4 (3.2 to 26.7)
        Week 52 n=34,27,35
    5.9 (0.7 to 19.7)
    0 (0.0 to 12.8)
    5.7 (0.7 to 19.2)
    No statistical analyses for this end point

    Secondary: Duration of biochemical response (DBR), by treatment (Full Analysis Set)

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    End point title
    		 Duration of biochemical response (DBR), by treatment (Full Analysis Set)
    End point description
    Time from the first documentation of biochemical response to the first documentation of biochemical progression or to death due to any cause, whichever occurred first. Biochemical progression is defined as an increase of serum CgA levels ≥ 25% compared to baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 18
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    8
    4
    9
    Units: months
        median (confidence interval 95%)
    14.75 (0.03 to 99.9)
    2.00 (0.03 to 99.9)
    8.38 (0.03 to 99.9)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier event-free probability estimate based on CgA levels

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    End point title
    		 Kaplan-Meier event-free probability estimate based on CgA levels
    End point description
    Kaplan Meier estimates are for Duration of biochemical response (DBR) outcome measure. Events are biochemical progressions i.e. an increase of CgA levels >= 25% compared to baseline or deaths due to any cause. Percent (%) Event-free probability estimate is the estimated probability that a patient will remain event-free up to the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to Month 18
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    8
    4
    9
    Units: event free probability estimates
    number (confidence interval 95%)
        3 months
    75.0 (31.5 to 93.1)
    37.5 (1.1 to 80.8)
    77.8 (36.5 to 93.9)
        6 months
    56.3 (14.7 to 84.2)
    999.9 (999.9 to 999.9)
    77.8 (36.5 to 93.9)
        9 months
    56.3 (14.7 to 84.2)
    999.9 (999.9 to 999.9)
    44.4 (13.6 to 71.9)
        12 months
    56.3 (14.7 to 84.2)
    999.9 (999.9 to 999.9)
    44.4 (13.6 to 71.9)
        15 months
    37.5 (5.6 to 71.7)
    999.9 (999.9 to 999.9)
    44.4 (13.6 to 71.9)
        18 months
    37.5 (5.6 to 71.7)
    999.9 (999.9 to 999.9)
    44.4 (13.6 to 71.9)
    No statistical analyses for this end point

    Secondary: Summary of biochemical progression-free survival based on CgA levels by treatment

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    End point title
    		 Summary of biochemical progression-free survival based on CgA levels by treatment
    End point description
    Time from the first documentation of biochemical response to the first documentation of biochemical progression or to death due to any cause, whichever occurred first. Biochemical progression is defined as an increase of serum CgA levels ≥ 25% compared to baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up Month 24
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    41
    42
    41
    Units: months
        median (confidence interval 95%)
    2.89 (2.79 to 5.49)
    2.86 (2.79 to 3.52)
    5.62 (3.9 to 8.31)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier event-free probability estimate for biochemical progression-free survival based on CgA levels

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    End point title
    		 Kaplan-Meier event-free probability estimate for biochemical progression-free survival based on CgA levels
    End point description
    Percent (%) Event-free probability estimate is the estimated probability that a patient will remain event-free up to the specified time point. Percent event-free probability estimates are obtained from the Kaplan-Meier survival estimates. Events are biochemical progressions, i.e., an increase of CgA levels >= 25% compared to baseline or deaths due to any cause.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to Month 24
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    41
    42
    41
    Units: event free probability estimates
    number (confidence interval 95%)
        3 months
    43.1 (26.4 to 58.6)
    35.4 (20.0 to 51.1)
    77.1 (59.4 to 87.8)
        6 months
    29.5 (15.0 to 45.6)
    17.7 (7.2 to 32.0)
    44.5 (27.6 to 60.0)
        9 months
    18.5 (7.1 to 34.0)
    11.0 (3.2 to 24.5)
    29.7 (15.5 to 45.2)
        12 months
    18.5 (7.1 to 34.0)
    7.4 (1.4 to 20.0)
    26.4 (13.0 to 41.9)
        15 months
    18.5 (7.1 to 34.0)
    999.9 (999.9 to 999.9)
    18.1 (6.7 to 33.8)
        18 months
    13.8 (4.1 to 29.4)
    999.9 (999.9 to 999.9)
    18.1 (6.7 to 33.8)
        21 months
    13.8 (4.1 to 29.4)
    999.9 (999.9 to 999.9)
    18.1 (6.7 to 33.8)
        24 months
    999.9 (999.9 to 999.9)
    999.9 (999.9 to 999.9)
    18.1 (6.7 to 33.8)
    No statistical analyses for this end point

    Secondary: Biochemical response rate (BRR) for 5HIAA levels

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    End point title
    		 Biochemical response rate (BRR) for 5HIAA levels
    End point description
    The percentages are the biochemical response rates i.e. percentage of patients showing normalization i.e. return to within normal ranges, or a decrease of >= 50% from baseline of 5HIAA concentrations.
    End point type
    Secondary
    End point timeframe
    Baseline up Week 52
    End point values
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Number of subjects analysed
    20
    18
    20
    Units: percentage of participants
    number (confidence interval 95%)
        Week 12
    20.0 (5.7 to 43.7)
    11.1 (1.4 to 34.7)
    10.0 (1.2 to 31.7)
        Week 24
    5.0 (0.1 to 24.9)
    11.1 (1.4 to 34.7)
    20.0 (5.7 to 43.7)
        Week 36
    5.0 (0.1 to 24.9)
    11.1 (1.4 to 34.7)
    5.0 (0.1 to 24.9)
        Week 48
    5.0 (0.1 to 24.9)
    0 (0.0 to 18.5)
    5.0 (0.1 to 24.9)
        Week 52
    5.0 (0.1 to 24.9)
    0 (0.0 to 18.5)
    10.0 (1.2 to 31.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment up to maximum duration of 316 weeks
    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
    22.0
    Reporting groups
    Reporting group title
    Pasireotide LAR
    Reporting group description
    		 Pasireotide LAR

    Reporting group title
    Everolimus
    Reporting group description
    		 Everolimus

    Reporting group title
    Pasireotide LAR and Everolimus Combination
    Reporting group description
    		 Pasireotide LAR and Everolimus Combination

    Serious adverse events
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 41 (41.46%)
    20 / 42 (47.62%)
    16 / 41 (39.02%)
         number of deaths (all causes)
    2
    7
    3
         number of deaths resulting from adverse events
    0
    1
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Axillary pain
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Face oedema
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 42 (4.76%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 42 (7.14%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 42 (7.14%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Hydrothorax
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 42 (4.76%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    C-reactive protein increased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria traumatic
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation oesophagitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Tachycardia paroxysmal
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Brain compression
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Spinal cord compression
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Constipation
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 42 (7.14%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Dysphagia
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salivary gland pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 42 (2.38%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystocholangitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin haemorrhage
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    Anuria
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Carcinoid crisis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carcinoid syndrome
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cushing's syndrome
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Aspergillus infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 41 (12.20%)
    2 / 42 (4.76%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Diabetes mellitus
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperammonaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hyponatraemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metabolic acidosis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pasireotide LAR Everolimus Pasireotide LAR and Everolimus Combination
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 41 (97.56%)
    42 / 42 (100.00%)
    40 / 41 (97.56%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 42 (4.76%)
    4 / 41 (9.76%)
         occurrences all number
    1
    2
    5
    Hypertension
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 42 (4.76%)
    3 / 41 (7.32%)
         occurrences all number
    6
    8
    4
    Hypotension
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 42 (4.76%)
    1 / 41 (2.44%)
         occurrences all number
    3
    2
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 41 (26.83%)
    12 / 42 (28.57%)
    16 / 41 (39.02%)
         occurrences all number
    20
    28
    48
    Chills
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    4
    0
    0
    Fatigue
         subjects affected / exposed
    6 / 41 (14.63%)
    9 / 42 (21.43%)
    16 / 41 (39.02%)
         occurrences all number
    10
    13
    26
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 41 (7.32%)
    4 / 42 (9.52%)
    3 / 41 (7.32%)
         occurrences all number
    3
    6
    4
    Oedema peripheral
         subjects affected / exposed
    8 / 41 (19.51%)
    13 / 42 (30.95%)
    12 / 41 (29.27%)
         occurrences all number
    9
    25
    21
    Pyrexia
         subjects affected / exposed
    7 / 41 (17.07%)
    7 / 42 (16.67%)
    6 / 41 (14.63%)
         occurrences all number
    9
    12
    13
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 41 (21.95%)
    12 / 42 (28.57%)
    14 / 41 (34.15%)
         occurrences all number
    10
    19
    19
    Dyspnoea
         subjects affected / exposed
    8 / 41 (19.51%)
    11 / 42 (26.19%)
    6 / 41 (14.63%)
         occurrences all number
    12
    15
    11
    Epistaxis
         subjects affected / exposed
    0 / 41 (0.00%)
    5 / 42 (11.90%)
    3 / 41 (7.32%)
         occurrences all number
    0
    6
    3
    Haemoptysis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    3 / 41 (7.32%)
         occurrences all number
    0
    1
    3
    Pneumonitis
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
    4 / 41 (9.76%)
         occurrences all number
    0
    2
    4
    Productive cough
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
    7 / 41 (17.07%)
         occurrences all number
    0
    2
    10
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 42 (9.52%)
    3 / 41 (7.32%)
         occurrences all number
    2
    4
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 42 (7.14%)
    3 / 41 (7.32%)
         occurrences all number
    6
    3
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 41 (9.76%)
    3 / 42 (7.14%)
    1 / 41 (2.44%)
         occurrences all number
    5
    4
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 41 (17.07%)
    2 / 42 (4.76%)
    2 / 41 (4.88%)
         occurrences all number
    15
    3
    3
    Blood creatinine increased
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 42 (2.38%)
    3 / 41 (7.32%)
         occurrences all number
    4
    3
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    10 / 41 (24.39%)
    4 / 42 (9.52%)
    4 / 41 (9.76%)
         occurrences all number
    15
    6
    9
    Glycosylated haemoglobin increased
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 42 (2.38%)
    3 / 41 (7.32%)
         occurrences all number
    4
    1
    4
    Platelet count decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    3 / 41 (7.32%)
         occurrences all number
    0
    1
    5
    Weight decreased
         subjects affected / exposed
    18 / 41 (43.90%)
    18 / 42 (42.86%)
    24 / 41 (58.54%)
         occurrences all number
    30
    30
    47
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 42 (2.38%)
    1 / 41 (2.44%)
         occurrences all number
    5
    1
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 41 (14.63%)
    2 / 42 (4.76%)
    2 / 41 (4.88%)
         occurrences all number
    7
    4
    2
    Dysgeusia
         subjects affected / exposed
    4 / 41 (9.76%)
    5 / 42 (11.90%)
    4 / 41 (9.76%)
         occurrences all number
    4
    5
    4
    Headache
         subjects affected / exposed
    7 / 41 (17.07%)
    4 / 42 (9.52%)
    6 / 41 (14.63%)
         occurrences all number
    12
    9
    8
    Presyncope
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    4
    0
    0
    Taste disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 41 (21.95%)
    14 / 42 (33.33%)
    10 / 41 (24.39%)
         occurrences all number
    21
    21
    16
    Leukopenia
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 42 (7.14%)
    3 / 41 (7.32%)
         occurrences all number
    0
    4
    3
    Thrombocytopenia
         subjects affected / exposed
    0 / 41 (0.00%)
    9 / 42 (21.43%)
    7 / 41 (17.07%)
         occurrences all number
    0
    16
    14
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    15 / 41 (36.59%)
    6 / 42 (14.29%)
    6 / 41 (14.63%)
         occurrences all number
    28
    6
    8
    Abdominal pain upper
         subjects affected / exposed
    5 / 41 (12.20%)
    5 / 42 (11.90%)
    3 / 41 (7.32%)
         occurrences all number
    9
    6
    6
    Aphthous ulcer
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 42 (7.14%)
    0 / 41 (0.00%)
         occurrences all number
    0
    11
    0
    Constipation
         subjects affected / exposed
    9 / 41 (21.95%)
    6 / 42 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    12
    8
    0
    Diarrhoea
         subjects affected / exposed
    17 / 41 (41.46%)
    21 / 42 (50.00%)
    33 / 41 (80.49%)
         occurrences all number
    76
    46
    103
    Dyspepsia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    1
    0
    3
    Dysphagia
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 42 (9.52%)
    0 / 41 (0.00%)
         occurrences all number
    0
    9
    0
    Flatulence
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 42 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    2
    0
    6
    Haemorrhoids
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 42 (2.38%)
    4 / 41 (9.76%)
         occurrences all number
    3
    2
    4
    Mouth ulceration
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 42 (7.14%)
    6 / 41 (14.63%)
         occurrences all number
    0
    4
    12
    Nausea
         subjects affected / exposed
    11 / 41 (26.83%)
    10 / 42 (23.81%)
    8 / 41 (19.51%)
         occurrences all number
    21
    16
    10
    Steatorrhoea
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 42 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    6
    0
    3
    Stomatitis
         subjects affected / exposed
    2 / 41 (4.88%)
    26 / 42 (61.90%)
    14 / 41 (34.15%)
         occurrences all number
    2
    50
    29
    Toothache
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 42 (2.38%)
    4 / 41 (9.76%)
         occurrences all number
    2
    1
    4
    Vomiting
         subjects affected / exposed
    5 / 41 (12.20%)
    5 / 42 (11.90%)
    4 / 41 (9.76%)
         occurrences all number
    11
    5
    5
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 42 (7.14%)
    4 / 41 (9.76%)
         occurrences all number
    0
    4
    4
    Onychoclasis
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 42 (7.14%)
    3 / 41 (7.32%)
         occurrences all number
    0
    3
    4
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 42 (7.14%)
    2 / 41 (4.88%)
         occurrences all number
    0
    3
    2
    Pruritus
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 42 (4.76%)
    7 / 41 (17.07%)
         occurrences all number
    2
    2
    11
    Rash
         subjects affected / exposed
    3 / 41 (7.32%)
    12 / 42 (28.57%)
    6 / 41 (14.63%)
         occurrences all number
    3
    22
    11
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 42 (4.76%)
    1 / 41 (2.44%)
         occurrences all number
    3
    2
    1
    Polyuria
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    1
    0
    3
    Renal failure
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 42 (9.52%)
    0 / 41 (0.00%)
         occurrences all number
    2
    6
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 42 (2.38%)
    3 / 41 (7.32%)
         occurrences all number
    6
    2
    4
    Back pain
         subjects affected / exposed
    10 / 41 (24.39%)
    6 / 42 (14.29%)
    7 / 41 (17.07%)
         occurrences all number
    13
    7
    7
    Bone pain
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 42 (4.76%)
    3 / 41 (7.32%)
         occurrences all number
    3
    2
    3
    Joint swelling
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 42 (2.38%)
    3 / 41 (7.32%)
         occurrences all number
    2
    1
    3
    Muscle spasms
         subjects affected / exposed
    5 / 41 (12.20%)
    2 / 42 (4.76%)
    1 / 41 (2.44%)
         occurrences all number
    6
    2
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 41 (9.76%)
    2 / 42 (4.76%)
    2 / 41 (4.88%)
         occurrences all number
    4
    2
    3
    Musculoskeletal pain
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 42 (2.38%)
    2 / 41 (4.88%)
         occurrences all number
    4
    1
    2
    Neck pain
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences all number
    3
    1
    0
    Pain in extremity
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 42 (2.38%)
    4 / 41 (9.76%)
         occurrences all number
    3
    1
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 42 (7.14%)
    1 / 41 (2.44%)
         occurrences all number
    11
    3
    1
    Cystitis
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 42 (9.52%)
    0 / 41 (0.00%)
         occurrences all number
    1
    5
    0
    Folliculitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    4 / 41 (9.76%)
         occurrences all number
    0
    1
    6
    Influenza
         subjects affected / exposed
    5 / 41 (12.20%)
    2 / 42 (4.76%)
    2 / 41 (4.88%)
         occurrences all number
    9
    3
    6
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    4 / 41 (9.76%)
         occurrences all number
    0
    1
    4
    Rhinitis
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences all number
    3
    2
    0
    Urinary tract infection
         subjects affected / exposed
    4 / 41 (9.76%)
    2 / 42 (4.76%)
    7 / 41 (17.07%)
         occurrences all number
    4
    12
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 41 (24.39%)
    16 / 42 (38.10%)
    13 / 41 (31.71%)
         occurrences all number
    13
    24
    20
    Diabetes mellitus
         subjects affected / exposed
    9 / 41 (21.95%)
    4 / 42 (9.52%)
    8 / 41 (19.51%)
         occurrences all number
    13
    4
    13
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    7 / 42 (16.67%)
    5 / 41 (12.20%)
         occurrences all number
    1
    8
    5
    Hyperglycaemia
         subjects affected / exposed
    18 / 41 (43.90%)
    14 / 42 (33.33%)
    36 / 41 (87.80%)
         occurrences all number
    43
    32
    123
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 41 (7.32%)
    9 / 42 (21.43%)
    5 / 41 (12.20%)
         occurrences all number
    5
    14
    7
    Hypoglycaemia
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 42 (4.76%)
    3 / 41 (7.32%)
         occurrences all number
    5
    2
    4
    Hypokalaemia
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 42 (7.14%)
    5 / 41 (12.20%)
         occurrences all number
    2
    4
    6
    Hypomagnesaemia
         subjects affected / exposed
    4 / 41 (9.76%)
    2 / 42 (4.76%)
    3 / 41 (7.32%)
         occurrences all number
    6
    2
    5
    Hyponatraemia
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 42 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    2
    0
    4
    Hypophosphataemia
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 42 (7.14%)
    5 / 41 (12.20%)
         occurrences all number
    1
    6
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Nov 2011
    The original version (finalized on 06-Oct-2011) of the study protocol was amended before submission to Competent Authorities/Ethics Committee to increase the hepatic-related safety measures for patients treated with pasireotide LAR.
    11 Dec 2012
    The study protocol was amended mainly to clarify the importance of routine patient glucose self-monitoring, to detect and treat hyperglycemia as early as possible, and to give specific guidance on dose adjustment in the different treatment arms.
    16 Jul 2013
    Amendment was in part to satisfy requests from Competent Authority to: Implement an exclusion criterion for female patients pregnant and breast-feeding, impleement a more frequent monitoring of the Thyroid Function Tests, implement a more detailed guidance for physicians in the response to a QTc prolongation on ECG and also to update the Pasireotide LAR IB edition 13 dated 24-May-2013.
    07 Oct 2014
    Protocol was amended mainly to remove the replacement policy (to avoid the introduction of biases in the study), to change the timepoint at which the primary endpoint was evaluated (from month 12 to month 9) and to update information on everolimus and pasireotide LAR based on the new versions of the respective Investigator Brochures (ed. 13, 12-May-2014 for everolimus; ed. 14, 02-Jun-2014 for pasireotide LAR).
    07 Nov 2016
    The protocol amendment modified the duration of the extension phase from ‘until disease progression’ to ‘until they no longer demonstrate benefit or fulfill any of the study discontinuation criteria’. The end of study definition was modified from ‘the last visit 2 years after the start of treatment of the last randomized patient or when all patients have progressed whichever comes first’ to ‘when all patients have discontinued the study’.

    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.
    The EudraCT system does not accept NA. The EMA work around is that 999 is entered to represent “not available”, “not estimable” or “not evaluable” data.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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