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    Clinical Trial Results:
    A randomized, open-label Phase II multicenter study evaluating the efficacy of oral everolimus alone or in combination with pasireotide LAR im in advanced progressive pancreatic neuroendocrine tumors (PNET) – The COOPERATE-2 study

    Summary
    EudraCT number
    		 2010-023183-40
    Trial protocol
    		 GB   SE   BE   DK   DE   HU   ES   NL   IT  
    Global end of trial date
    19 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    13 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSOM230I2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01374451
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4004, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to estimate the treatment effect of everolimus in combination with pasireotide LAR relative to everolimus alone on progression-free survival (PFS) in patients with advanced PNET and to assess the predictive probability of success in a possible subsequent Phase III study once 80 PFS events have been observed.
    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
    20 Jun 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Thailand: 5
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    160
    EEA total number of subjects
    112
    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)
    114
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients were randomized in a 1:1 ratio to receive everolimus or everolimus + pasireotide LAR. Randomization was by stratification. Approximately 150 patients were planned to be randomized globally. For each patient there were 3 separate periods in the study: screening/baseline, treatment and follow-up.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Paseriotide LAR + Everolimus
    Arm description
    		 everolimus 10 mg once daily po in combination with pasireotide LAR 60 mg every 28 days (q28d) im
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paseriotide LAR
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide LAR im depot injections were supplied as a powder in vials containing 20 mg and 40 mg with ampoules containing 2 mL of vehicle for reconstitution.

    Arm title
    		 Everolimus
    Arm description
    		 everolimus 10 mg once daily po alone
    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
    Everolimus was supplied as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets.

    Number of subjects in period 1
    		Paseriotide LAR + Everolimus Everolimus
    Started
    79
    81
    Completed
    78
    81
    Not completed
    1
    0
         Administrative problems
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Paseriotide LAR + Everolimus
    Reporting group description
    		 everolimus 10 mg once daily po in combination with pasireotide LAR 60 mg every 28 days (q28d) im

    Reporting group title
    Everolimus
    Reporting group description
    		 everolimus 10 mg once daily po alone

    Reporting group values
    		 Paseriotide LAR + Everolimus Everolimus Total
    Number of subjects
    		 79 81 160
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 59 55 114
        From 65-84 years
    		 20 26 46
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.52 ± 11.978 58.22 ± 12.65 -
    Gender, Male/Female
    Units: Participants
        Female
    		 40 34 74
        Male
    		 39 47 86

    End points

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    End points reporting groups
    Reporting group title
    Paseriotide LAR + Everolimus
    Reporting group description
    		 everolimus 10 mg once daily po in combination with pasireotide LAR 60 mg every 28 days (q28d) im

    Reporting group title
    Everolimus
    Reporting group description
    		 everolimus 10 mg once daily po alone

    Primary: Progression-free survival (PFS) per local radiological review

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    End point title
    		 Progression-free survival (PFS) per local radiological review
    End point description
    PFS per RECIST 1.0. (Response Evaluation Criteria in Solid Tumors). PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause.
    End point type
    Primary
    End point timeframe
    Once 80 PFS events had occurred aproximately after 24 months
    End point values
    		 Paseriotide LAR + Everolimus Everolimus
    Number of subjects analysed
    79
    81
    Units: months
        median (confidence interval 95%)
    16.82 (12.09 to 19.58)
    16.59 (11.07 to 19.48)
    Statistical analysis title
    		 PFS based on local radiological review
    Comparison groups
    Everolimus v Paseriotide LAR + Everolimus
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.488
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.991
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.636
         upper limit
    		 1.543
    Variability estimate
    Standard deviation

    Secondary: Safety and tolerability profile of Everolimus alone or in combination with Pasireotide LAR

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    End point title
    		 Safety and tolerability profile of Everolimus alone or in combination with Pasireotide LAR
    End point description
    Consisted of monitoring and recording the rate, type, severity, and causal relationship of adverse events (AEs) and serious AEs (SAEs) to treatment. The safety analysis was based mainly on the frequency of AEs or SAEs and on the number of laboratory values that fell outside of pre-determined range.
    End point type
    Secondary
    End point timeframe
    Once 80 PFS events had occurred
    End point values
    		 Paseriotide LAR + Everolimus Everolimus
    Number of subjects analysed
    78
    81
    Units: Participants
        Deaths
    7
    10
        Serious Adverse Events
    41
    49
        Adverse Events
    78
    81
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) as per radiology review

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    End point title
    		 Objective Response Rate (ORR) as per radiology review
    End point description
    Objective response was determined by the local radiologist according to the RECIST Version 1.0. ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR). This is also referred to as Overall response rate. CR: Disappearance of all nontarget lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameter of all target lesions recorded at or after baseline.
    End point type
    Secondary
    End point timeframe
    Once 80 PFS events had occurred
    End point values
    		 Paseriotide LAR + Everolimus Everolimus
    Number of subjects analysed
    79
    81
    Units: Percentage of participants
        number (confidence interval 95%)
    20.3 (12 to 30.8)
    6.2 (2 to 13.8)
    No statistical analyses for this end point

    Secondary: Duration of response (DoR)

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    End point title
    		 Duration of response (DoR)
    End point description
    Analyzed in patients with best overall response of complete response (CR) or partial response (PR). The start date was the date of first documented response (CR or PR) and the end date was defined as the first documented progression or death due to underlying cancer. If a patient had not had an event or when receiving any further anti-cancer therapy, DoR was censored at the date of last adequate tumor assessment. Based on the mode of action of everolimus and pasireotide and based on current experience, only a low number of objective responses per RECIST were expected. Therefore, DoR was listed with confirmed responses flagged in the listing.
    End point type
    Secondary
    End point timeframe
    Once 80 PFS events had occurred
    End point values
    		 Paseriotide LAR + Everolimus Everolimus
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: Months
        number (not applicable)
    Notes
    [1] - A low number of objective responses per RECIST was expected. Duration of response was not analyzed.
    [2] - A low number of objective responses per RECIST was expected. Duration of response was not analyzed.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) using Kaplan Meier method

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    End point title
    		 Overall Survival (OS) using Kaplan Meier method
    End point description
    Overall survival was defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival was to be censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    Once 80 PFS events had occurred
    End point values
    		 Paseriotide LAR + Everolimus Everolimus
    Number of subjects analysed
    79
    81
    Units: Percentage of participants
    arithmetic mean (confidence interval 95%)
        6 months
    93.5 (85 to 97.2)
    93.7 (85.5 to 97.3)
        12 months
    85.5 (75.4 to 91.7)
    86.1 (76.2 to 92)
        18 months
    81.4 (70.6 to 88.5)
    75.5 (64.3 to 83.6)
        24 months
    77 (65.6 to 85.1)
    71 (59.3 to 79.9)
    No statistical analyses for this end point

    Secondary: PFS and the predictive probability of success in phase III

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    End point title
    		 PFS and the predictive probability of success in phase III
    End point description
    Since the study was terminated because the study did not meet its primary objective which was based on PFS as per local radiology assessment, minimal efficacy data was obtained. Only 80 PFS events occurred before study was terminated so 105 PFS events was not reached to analyze this data.
    End point type
    Secondary
    End point timeframe
    Once 105 PFS events had occurred occurred
    End point values
    		 Paseriotide LAR + Everolimus Everolimus
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Months
        number (not applicable)
    Notes
    [3] - 80 PFS events occurred before study was terminated. 105 PFS events was not reached to analyze data.
    [4] - 80 PFS events occurred before study was terminated. 105 PFS events was not reached to analyze data.
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) as per radiology review

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    End point title
    		 Disease Control Rate (DCR) as per radiology review
    End point description
    Disease control rate is the percentage of patients with a best overall response of CR or PR or stable disease (SD) determined by the local radiologist according to the Response Evaluation Criteria In Solid Tumors Criteria (RECIST) Version 1.0. CR: Disappearance of all nontarget lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameter of all target lesions recorded at or after baseline. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD). PD: Any progression ≤ 18 weeks after randomization (and not qualifying for CR, PR or stable disease SD.
    End point type
    Secondary
    End point timeframe
    Once 80 PFS events had occurred
    End point values
    		 Paseriotide LAR + Everolimus Everolimus
    Number of subjects analysed
    79
    81
    Units: Percentage of participants
        number (confidence interval 95%)
    77.2 (66.4 to 85.9)
    82.7 (72.7 to 90.2)
    No statistical analyses for this end point

    Secondary: Summary of Pharmacokinetics (PK) for everolimus for AUClast

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    End point title
    		 Summary of Pharmacokinetics (PK) for everolimus for AUClast
    End point description
    PK analysis set consisted of all patients who had at least 1 pasireotide LAR injection or 1 everolimus administration and 1 evaluable concentration data.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1
    End point values
    		 Paseriotide LAR + Everolimus Everolimus
    Number of subjects analysed
    5
    8
    Units: ng*hr/mL
        arithmetic mean (standard deviation)
    511 ± 91.8
    378 ± 123
    No statistical analyses for this end point

    Secondary: Summary of Pharmacokinetics (PK) for everolimus for CL/F

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    End point title
    		 Summary of Pharmacokinetics (PK) for everolimus for CL/F
    End point description
    PK analysis set consisted of all patients who had at least 1 pasireotide LAR injection or 1 everolimus administration and 1 evaluable concentration data.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1
    End point values
    		 Paseriotide LAR + Everolimus Everolimus
    Number of subjects analysed
    5
    8
    Units: L/hr
        arithmetic mean (standard deviation)
    20 ± 3.21
    29 ± 9.51
    No statistical analyses for this end point

    Secondary: Summary of Pharmacokinetics (PK) for everolimus for Cmax and Cmin

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    End point title
    		 Summary of Pharmacokinetics (PK) for everolimus for Cmax and Cmin
    End point description
    PK analysis set consisted of all patients who had at least 1 pasireotide LAR injection or 1 everolimus administration and 1 evaluable concentration data
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1
    End point values
    		 Paseriotide LAR + Everolimus Everolimus
    Number of subjects analysed
    6
    9
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cmax
    58.7 ± 25.9
    60.2 ± 30.6
        Cmin
    14.7 ± 4.81
    7.67 ± 4.41
    No statistical analyses for this end point

    Secondary: Summary of Pharmacokinetics (PK) for everolimus for Tmax

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    End point title
    		 Summary of Pharmacokinetics (PK) for everolimus for Tmax
    End point description
    PK analysis set consisted of all patients who had at least 1 pasireotide LAR injection or 1 everolimus administration and 1 evaluable concentration data.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1
    End point values
    		 Paseriotide LAR + Everolimus Everolimus
    Number of subjects analysed
    6
    9
    Units: hr
        median (inter-quartile range (Q1-Q3))
    1 (0.333 to 5)
    0.5 (0.5 to 5)
    No statistical analyses for this end point

    Secondary: Summary of pasireotide concentrations following intramuscular injection of pasireotide LAR 60mg

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    End point title
    		 Summary of pasireotide concentrations following intramuscular injection of pasireotide LAR 60mg [5]
    End point description
    PK analysis set consisted of all patients who had at least 1 pasireotide LAR injection or 1 everolimus administration and 1 evaluable concentration data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 21, Cycle 2 Day 29
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Summary statistics was not planned for this endpoint.
    End point values
    		 Paseriotide LAR + Everolimus
    Number of subjects analysed
    69
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 21 (n:69)
    21.6 ± 13.1
        Cycle 2 Day 29 (n: 64)
    19.9 ± 12.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    		 Everolimus

    Reporting group title
    Everolimus +Pasireotide
    Reporting group description
    		 Everolimus +Pasireotide

    Serious adverse events
    		 Everolimus Everolimus +Pasireotide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 81 (60.49%)
    41 / 78 (52.56%)
         number of deaths (all causes)
    10
    7
         number of deaths resulting from adverse events
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrinoma
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperaemia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 81 (7.41%)
    5 / 78 (6.41%)
         occurrences causally related to treatment / all
    2 / 9
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 81 (3.70%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood albumin decreased
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 81 (2.47%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose fluctuation
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foreign body aspiration
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skeletal injury
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 81 (6.17%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Ocular icterus
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 81 (6.17%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    2 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal oedema
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids thrombosed
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 81 (3.70%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 81 (3.70%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    3 / 81 (3.70%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    3 / 81 (3.70%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis aeromonas
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex meningoencephalitis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 81 (2.47%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 81 (4.94%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Sinusitis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 81 (1.23%)
    5 / 78 (6.41%)
         occurrences causally related to treatment / all
    0 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Everolimus Everolimus +Pasireotide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 81 (98.77%)
    77 / 78 (98.72%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 81 (2.47%)
    6 / 78 (7.69%)
         occurrences all number
    5
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 81 (4.94%)
    7 / 78 (8.97%)
         occurrences all number
    6
    7
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 81 (4.94%)
    5 / 78 (6.41%)
         occurrences all number
    5
    8
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 81 (1.23%)
    4 / 78 (5.13%)
         occurrences all number
    1
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    11 / 81 (13.58%)
    10 / 78 (12.82%)
         occurrences all number
    11
    12
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 81 (1.23%)
    4 / 78 (5.13%)
         occurrences all number
    1
    4
    Weight decreased
         subjects affected / exposed
    25 / 81 (30.86%)
    24 / 78 (30.77%)
         occurrences all number
    27
    28
    Haemoglobin decreased
         subjects affected / exposed
    7 / 81 (8.64%)
    2 / 78 (2.56%)
         occurrences all number
    8
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    14 / 81 (17.28%)
    15 / 78 (19.23%)
         occurrences all number
    16
    17
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 81 (6.17%)
    4 / 78 (5.13%)
         occurrences all number
    6
    6
    Dysgeusia
         subjects affected / exposed
    17 / 81 (20.99%)
    10 / 78 (12.82%)
         occurrences all number
    20
    11
    Headache
         subjects affected / exposed
    26 / 81 (32.10%)
    17 / 78 (21.79%)
         occurrences all number
    34
    39
    Paraesthesia
         subjects affected / exposed
    5 / 81 (6.17%)
    3 / 78 (3.85%)
         occurrences all number
    6
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 81 (24.69%)
    21 / 78 (26.92%)
         occurrences all number
    29
    37
    Leukopenia
         subjects affected / exposed
    7 / 81 (8.64%)
    3 / 78 (3.85%)
         occurrences all number
    10
    9
    Lymphopenia
         subjects affected / exposed
    4 / 81 (4.94%)
    4 / 78 (5.13%)
         occurrences all number
    4
    6
    Thrombocytopenia
         subjects affected / exposed
    9 / 81 (11.11%)
    8 / 78 (10.26%)
         occurrences all number
    20
    11
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 81 (19.75%)
    17 / 78 (21.79%)
         occurrences all number
    18
    27
    Fatigue
         subjects affected / exposed
    27 / 81 (33.33%)
    21 / 78 (26.92%)
         occurrences all number
    40
    27
    Influenza like illness
         subjects affected / exposed
    7 / 81 (8.64%)
    1 / 78 (1.28%)
         occurrences all number
    8
    2
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 81 (7.41%)
    1 / 78 (1.28%)
         occurrences all number
    6
    1
    Oedema peripheral
         subjects affected / exposed
    31 / 81 (38.27%)
    26 / 78 (33.33%)
         occurrences all number
    53
    30
    Peripheral swelling
         subjects affected / exposed
    4 / 81 (4.94%)
    4 / 78 (5.13%)
         occurrences all number
    5
    4
    Pyrexia
         subjects affected / exposed
    21 / 81 (25.93%)
    15 / 78 (19.23%)
         occurrences all number
    29
    24
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    8 / 81 (9.88%)
    7 / 78 (8.97%)
         occurrences all number
    11
    7
    Aphthous stomatitis
         subjects affected / exposed
    9 / 81 (11.11%)
    5 / 78 (6.41%)
         occurrences all number
    22
    5
    Abdominal pain upper
         subjects affected / exposed
    15 / 81 (18.52%)
    10 / 78 (12.82%)
         occurrences all number
    22
    11
    Abdominal pain
         subjects affected / exposed
    29 / 81 (35.80%)
    22 / 78 (28.21%)
         occurrences all number
    41
    46
    Constipation
         subjects affected / exposed
    18 / 81 (22.22%)
    11 / 78 (14.10%)
         occurrences all number
    28
    15
    Diarrhoea
         subjects affected / exposed
    43 / 81 (53.09%)
    49 / 78 (62.82%)
         occurrences all number
    79
    94
    Dysphagia
         subjects affected / exposed
    5 / 81 (6.17%)
    0 / 78 (0.00%)
         occurrences all number
    5
    0
    Flatulence
         subjects affected / exposed
    0 / 81 (0.00%)
    8 / 78 (10.26%)
         occurrences all number
    0
    8
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 81 (6.17%)
    3 / 78 (3.85%)
         occurrences all number
    5
    3
    Mouth ulceration
         subjects affected / exposed
    6 / 81 (7.41%)
    4 / 78 (5.13%)
         occurrences all number
    8
    7
    Nausea
         subjects affected / exposed
    24 / 81 (29.63%)
    27 / 78 (34.62%)
         occurrences all number
    48
    41
    Steatorrhoea
         subjects affected / exposed
    2 / 81 (2.47%)
    9 / 78 (11.54%)
         occurrences all number
    3
    9
    Stomatitis
         subjects affected / exposed
    51 / 81 (62.96%)
    46 / 78 (58.97%)
         occurrences all number
    95
    75
    Vomiting
         subjects affected / exposed
    15 / 81 (18.52%)
    22 / 78 (28.21%)
         occurrences all number
    26
    41
    Toothache
         subjects affected / exposed
    5 / 81 (6.17%)
    3 / 78 (3.85%)
         occurrences all number
    5
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    28 / 81 (34.57%)
    21 / 78 (26.92%)
         occurrences all number
    40
    30
    Dyspnoea
         subjects affected / exposed
    12 / 81 (14.81%)
    5 / 78 (6.41%)
         occurrences all number
    16
    5
    Epistaxis
         subjects affected / exposed
    20 / 81 (24.69%)
    5 / 78 (6.41%)
         occurrences all number
    24
    5
    Oropharyngeal pain
         subjects affected / exposed
    6 / 81 (7.41%)
    4 / 78 (5.13%)
         occurrences all number
    7
    5
    Pneumonitis
         subjects affected / exposed
    11 / 81 (13.58%)
    5 / 78 (6.41%)
         occurrences all number
    12
    6
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    3 / 81 (3.70%)
    4 / 78 (5.13%)
         occurrences all number
    3
    4
    Acne
         subjects affected / exposed
    7 / 81 (8.64%)
    1 / 78 (1.28%)
         occurrences all number
    9
    1
    Dermatitis acneiform
         subjects affected / exposed
    7 / 81 (8.64%)
    6 / 78 (7.69%)
         occurrences all number
    9
    7
    Dry skin
         subjects affected / exposed
    19 / 81 (23.46%)
    12 / 78 (15.38%)
         occurrences all number
    26
    12
    Nail disorder
         subjects affected / exposed
    5 / 81 (6.17%)
    4 / 78 (5.13%)
         occurrences all number
    5
    4
    Onychoclasis
         subjects affected / exposed
    8 / 81 (9.88%)
    5 / 78 (6.41%)
         occurrences all number
    9
    5
    Rash
         subjects affected / exposed
    25 / 81 (30.86%)
    20 / 78 (25.64%)
         occurrences all number
    37
    23
    Pruritus
         subjects affected / exposed
    18 / 81 (22.22%)
    12 / 78 (15.38%)
         occurrences all number
    29
    14
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 81 (4.94%)
    4 / 78 (5.13%)
         occurrences all number
    4
    4
    Insomnia
         subjects affected / exposed
    8 / 81 (9.88%)
    7 / 78 (8.97%)
         occurrences all number
    10
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 81 (16.05%)
    11 / 78 (14.10%)
         occurrences all number
    16
    14
    Back pain
         subjects affected / exposed
    14 / 81 (17.28%)
    11 / 78 (14.10%)
         occurrences all number
    20
    15
    Muscle spasms
         subjects affected / exposed
    4 / 81 (4.94%)
    6 / 78 (7.69%)
         occurrences all number
    6
    12
    Musculoskeletal pain
         subjects affected / exposed
    5 / 81 (6.17%)
    4 / 78 (5.13%)
         occurrences all number
    7
    5
    Myalgia
         subjects affected / exposed
    7 / 81 (8.64%)
    6 / 78 (7.69%)
         occurrences all number
    9
    6
    Pain in extremity
         subjects affected / exposed
    8 / 81 (9.88%)
    11 / 78 (14.10%)
         occurrences all number
    10
    15
    Neck pain
         subjects affected / exposed
    5 / 81 (6.17%)
    2 / 78 (2.56%)
         occurrences all number
    5
    2
    Infections and infestations
    Cystitis
         subjects affected / exposed
    3 / 81 (3.70%)
    7 / 78 (8.97%)
         occurrences all number
    8
    9
    Gastroenteritis
         subjects affected / exposed
    3 / 81 (3.70%)
    4 / 78 (5.13%)
         occurrences all number
    3
    5
    Influenza
         subjects affected / exposed
    6 / 81 (7.41%)
    5 / 78 (6.41%)
         occurrences all number
    7
    5
    Nasopharyngitis
         subjects affected / exposed
    10 / 81 (12.35%)
    12 / 78 (15.38%)
         occurrences all number
    12
    27
    Pneumonia
         subjects affected / exposed
    5 / 81 (6.17%)
    1 / 78 (1.28%)
         occurrences all number
    7
    1
    Pharyngitis
         subjects affected / exposed
    2 / 81 (2.47%)
    5 / 78 (6.41%)
         occurrences all number
    2
    6
    Oral herpes
         subjects affected / exposed
    6 / 81 (7.41%)
    3 / 78 (3.85%)
         occurrences all number
    6
    3
    Rhinitis
         subjects affected / exposed
    5 / 81 (6.17%)
    1 / 78 (1.28%)
         occurrences all number
    6
    1
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 81 (7.41%)
    5 / 78 (6.41%)
         occurrences all number
    6
    5
    Urinary tract infection
         subjects affected / exposed
    5 / 81 (6.17%)
    4 / 78 (5.13%)
         occurrences all number
    6
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    22 / 81 (27.16%)
    14 / 78 (17.95%)
         occurrences all number
    30
    17
    Diabetes mellitus
         subjects affected / exposed
    6 / 81 (7.41%)
    20 / 78 (25.64%)
         occurrences all number
    6
    20
    Hypercholesterolaemia
         subjects affected / exposed
    15 / 81 (18.52%)
    16 / 78 (20.51%)
         occurrences all number
    17
    27
    Hyperglycaemia
         subjects affected / exposed
    23 / 81 (28.40%)
    56 / 78 (71.79%)
         occurrences all number
    32
    111
    Hypertriglyceridaemia
         subjects affected / exposed
    7 / 81 (8.64%)
    10 / 78 (12.82%)
         occurrences all number
    12
    18
    Hypoglycaemia
         subjects affected / exposed
    3 / 81 (3.70%)
    16 / 78 (20.51%)
         occurrences all number
    4
    23
    Hypokalaemia
         subjects affected / exposed
    11 / 81 (13.58%)
    5 / 78 (6.41%)
         occurrences all number
    16
    6
    Hyponatraemia
         subjects affected / exposed
    2 / 81 (2.47%)
    4 / 78 (5.13%)
         occurrences all number
    2
    4
    Hypophosphataemia
         subjects affected / exposed
    3 / 81 (3.70%)
    9 / 78 (11.54%)
         occurrences all number
    5
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2011
    The reason for this protocol amendment was to reflect an urgent safety measure. Monitoring of hepatic function was increased, inclusion and exclusion criteria were updated to increase hepatic safety and clear stopping rules for liver-related AEs were specified. This was based on findings in the pasireotide clinical development program, where three cases meeting Hy’s law criteria in healthy volunteers and one patient treated with pasireotide solution for s.c. injection was dentified. This was communicated in an Investigator Notification on October 31, 2011.
    17 Jul 2012
    Primary reason for this amendment was 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. In addition, sections of the protocol were updated and aligned, and corrections and clarifications were made. These modifications were not believed to have influenced the study outcome and did not impact the patient population studied. As of July 3, 2012, 100 patients had been randomized in the SOM230I2201 study.
    15 Nov 2012
    The reason for this amendment was that the Danish Health Authority did not consider total abstinence as a ‘highly effective contraception’ method. These modifications are not believed to have influenced the study outcome and did not impact the patient population studied. As of October 23, 2012, 139 patients had been randomized in the SOM230I2201 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.
    A planned primary analysis was completed with data cut of 02-Apr-2014. The study did not meet its primary objective, which was based on progression-free survival as per local radiology assessment and was prematurely terminated.
    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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