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    Clinical Trial Results:
    PHASE II, MULTICENTRE, OPEN LABEL STUDY TO EVALUATE THE EFFICACY OF THE COMBINATION OF LANREOTIDE AUTOGEL 120 MG AND TEMOZOLOMIDE IN PATIENTS WITH PROGRESSIVE GASTRO-ENTERO-PANCREATIC NEUROENDOCRINE TUMOURS (GEP-NET) G1/G2 - A PILOT-STUDY

    Summary
    EudraCT number
    		 2013-001697-17
    Trial protocol
    		 AT   DE  
    Global end of trial date
    01 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Aug 2018
    First version publication date
    03 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A-94-52030-268
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02231762
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IPSEN Pharma GmbH
    Sponsor organisation address
    Willy-Brandt-Str. 3, Ettlingen, Germany, 76275
    Public contact
    Medical Director, Ipsen, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Ipsen, clinical.trials@ipsen.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
    01 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary study objective was to evaluate the efficacy of lanreotide Autogel (ATG) 120 milligrams (mg) in combination with temozolomide in subjects with functioning as well as non-functioning, progressive, GEP-NET G1 or G2.
    Protection of trial subjects
    The study was conducted under the provision of the Declaration of Helsinki, in accordance with the International Council for Harmonisation Consolidated Guideline on Good Clinical Practice and in compliance with Independent Ethic Committees and informed consent regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Oct 2014
    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
    Austria: 15
    Country: Number of subjects enrolled
    Germany: 42
    Worldwide total number of subjects
    57
    EEA total number of subjects
    57
    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)
    29
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 57 subjects entered the combination phase and received lanreotide ATG 120 mg plus temozolomide for 6 months. A 6 month maintenance phase then followed where subjects received either lanreotide ATG 120 mg or no treatment, dependent upon whether they had functioning or non-functioning NET, clinical benefit and allocation following randomisation.

    Pre-assignment
    Screening details
    		 Overall, 64 subjects were screened, 7 were screening failures of which 5 subjects did not meet the entry criteria. 57 subjects were assigned to receive treatment in the baseline population.

    Period 1
    Period 1 title
    Combination Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Combination Phase
    Arm description
    		 All subjects received lanreotide ATG 120 mg plus temozolomide in combination for 6 months. Subjects received 1 injection of lanreotide ATG 120 mg and temozolomide capsules for 5 consecutive days, in a 28 day treatment cycle. The temozolomide dose was adapted to the subject body surface area (BSA) and the dose in the 1st treatment cycle was 150 mg/metres squared (m^2) per day. Depending on the safety laboratory values, the temozolomide dose was increased to 200 mg/m^2 per day from cycle 2 to cycle 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Temozolomide capsules were orally administered for 5 consecutive days every 28 days for 6 months. The capsules were presented as dose strength of 5 mg, 20 mg, 100 mg, or 250 mg. The dose for each treatment cycle was calculated according to the BSA of the subject. One treatment cycle was a period of 28 days. The dose in cycle 1 was 150 mg/m^2 per day and from cycle 2 to 6 it could be increased to 200 mg/m^2 per day. The BSA was monitored every 4 weeks and the temozolomide dose was calculated with a maximum of BSA of 2.0 m^2.

    Investigational medicinal product name
    Lanreotide ATG
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lanreotide ATG 120 mg, provided in a ready-to-use pre-filled syringe, was administered deep subcutaneously every 28 days for 6 months in the superior external quadrant of the buttock by a qualified person (no self or partner injection).

    Number of subjects in period 1
    		Combination Phase
    Started
    57
    Completed
    37
    Not completed
    20
         Consent withdrawn by subject
    2
         Disease progression
    6
         Did not meet inclusion criteria
    1
         Adverse event, non-fatal
    10
         Protocol deviation
    1
    Period 2
    Period 2 title
    Maintenance Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maintenance Phase - Functioning NET, Lanreotide
    Arm description
    		 In case of clinical benefit, defined as either complete response (CR), partial response (PR) or stable disease (SD) after the first 6 months combination phase, all subjects with functioning (serotonin producing) NET continued to receive lanreotide ATG 120 mg for another 6 months. This maintenance phase started with visit 8, week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide ATG
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lanreotide ATG 120 mg, provided in a ready-to-use pre-filled syringe, was administered deep subcutaneously every 28 days for 6 months in the superior external quadrant of the buttock by a qualified person (no self or partner injection).

    Arm title
    		 Maintenance Phase - Non-functioning NET, Lanreotide
    Arm description
    		 Following completion of the 6-month combination phase, all subjects with non-functioning NET and clinical benefit were randomised to continue to receive lanreotide ATG 120 mg for another 6 months. This maintenance phase started with visit 8, week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide ATG
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lanreotide ATG 120 mg, provided in a ready-to-use pre-filled syringe, was administered deep subcutaneously every 28 days for 6 months in the superior external quadrant of the buttock by a qualified person (no self or partner injection).

    Arm title
    		 Maintenance Phase - Non-functioning NET, No Treatment
    Arm description
    		 Following completion of the 6-month combination phase, all subjects with non-functioning NET and clinical benefit were randomised to receive no treatment for 6 months. This maintenance phase started with visit 8, week 24.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Maintenance Phase - Functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, No Treatment
    Started
    11
    14
    12
    Completed
    8
    9
    7
    Not completed
    3
    5
    5
         Disease progression
    3
    4
    3
         Adverse event, non-fatal
    -
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Combination Phase
    Reporting group description
    		 All subjects received lanreotide ATG 120 mg plus temozolomide in combination for 6 months. Subjects received 1 injection of lanreotide ATG 120 mg and temozolomide capsules for 5 consecutive days, in a 28 day treatment cycle. The temozolomide dose was adapted to the subject body surface area (BSA) and the dose in the 1st treatment cycle was 150 mg/metres squared (m^2) per day. Depending on the safety laboratory values, the temozolomide dose was increased to 200 mg/m^2 per day from cycle 2 to cycle 6.

    Reporting group values
    		 Combination Phase Total
    Number of subjects
    		 57
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.1 ± 11.0 -
    Gender categorical
    Units: Subjects
        Female
    		 24 24
        Male
    		 33 33
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native.
    		 0 0
        Asian.
    		 0 0
        Black or African American
    		 0 0
        Hispanic or Latino
    		 0 0
        Native Hawaiian or Other Pacific Islander.
    		 0 0
        White
    		 57 57

    End points

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    End points reporting groups
    Reporting group title
    Combination Phase
    Reporting group description
    		 All subjects received lanreotide ATG 120 mg plus temozolomide in combination for 6 months. Subjects received 1 injection of lanreotide ATG 120 mg and temozolomide capsules for 5 consecutive days, in a 28 day treatment cycle. The temozolomide dose was adapted to the subject body surface area (BSA) and the dose in the 1st treatment cycle was 150 mg/metres squared (m^2) per day. Depending on the safety laboratory values, the temozolomide dose was increased to 200 mg/m^2 per day from cycle 2 to cycle 6.
    Reporting group title
    Maintenance Phase - Functioning NET, Lanreotide
    Reporting group description
    		 In case of clinical benefit, defined as either complete response (CR), partial response (PR) or stable disease (SD) after the first 6 months combination phase, all subjects with functioning (serotonin producing) NET continued to receive lanreotide ATG 120 mg for another 6 months. This maintenance phase started with visit 8, week 24.

    Reporting group title
    Maintenance Phase - Non-functioning NET, Lanreotide
    Reporting group description
    		 Following completion of the 6-month combination phase, all subjects with non-functioning NET and clinical benefit were randomised to continue to receive lanreotide ATG 120 mg for another 6 months. This maintenance phase started with visit 8, week 24.

    Reporting group title
    Maintenance Phase - Non-functioning NET, No Treatment
    Reporting group description
    		 Following completion of the 6-month combination phase, all subjects with non-functioning NET and clinical benefit were randomised to receive no treatment for 6 months. This maintenance phase started with visit 8, week 24.

    Subject analysis set title
    Intention-to-treat (ITT) Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All treated subjects having at least one baseline and at least one post baseline assessment of the primary efficacy parameter.

    Subject analysis set title
    Combination Phase - Functioning NET
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects in the combination phase who were categorised at baseline as having functioning NET.

    Subject analysis set title
    Pharmacokinetic (PK) Subset
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects for whom PK assessments were performed and with evaluable PK data.

    Primary: Disease Control Rate (DCR) After 6 Months

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    End point title
    		 Disease Control Rate (DCR) After 6 Months [1]
    End point description
    All tumour assessments were performed using the Response Evaluation Criteria In Solid Tumours (RECIST) criteria (1.1). Computer Tomography (CT-scan) or Magnetic Resonance Imaging (MRI) could be used for as method of tumour measurement and the same method of tumour measurement was used throughout the study for each subject. CT scans/MRI were performed at screening or baseline visit then at weeks 12, 24 and at early withdrawal or at anytime during the study in the case of any clinical or biological signs of tumour progression. The DCR was defined as the proportion of subjects with a response of CR, PR or SD after 6 months of combination treatment and was described in the ITT population along with its 95% Confidence Interval (CI) and was compared to 45% with an exact binomial proportion test. The Last Observation Carried Forward (LOCF) method was used to replace missing assessments at the end of the combination phase.
    End point type
    Primary
    End point timeframe
    6 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the end point only reports on a single arm, no comparative analysis can be presented. A p value of <0.0001 was derived from an Exact Bionomial Proportion Test comparing the DCR to 45%.
    End point values
    		 Combination Phase
    Number of subjects analysed
    49
    Units: percentage of subjects
        number (confidence interval 95%)
    73.5 (58.9 to 85.1)
    No statistical analyses for this end point

    Secondary: DCR After 12 Months

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    End point title
    		 DCR After 12 Months
    End point description
    All tumour assessments were performed using the RECIST criteria (1.1). CT-scan or MRI could be used for as method of tumour measurement and the same method of tumour measurement was used throughout the study for each subject. CT scans/MRI were performed at screening or baseline visit then at weeks 12, 24, 36, 48 (end of study) and at study withdrawal or at anytime during the study in the case of any clinical or biological signs of tumour progression. The DCR was defined as the proportion of subjects with a response of CR, PR or SD after 6 months combination treatment followed by either 6 months of lanreotide ATG 120 mg maintenance treatment or no treatment. The DCR was described in the ITT population along with its 95% CI and was compared to 45% with an exact binomial proportion test. The LOCF method was used to replace missing assessments at the end of the maintenance phase.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Maintenance Phase - Functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, No Treatment
    Number of subjects analysed
    11
    14
    12
    Units: percentage of subjects
        number (confidence interval 95%)
    54.5 (23.4 to 83.3)
    71.4 (41.9 to 91.6)
    41.7 (15.2 to 72.3)
    No statistical analyses for this end point

    Secondary: Progression–Free Survival (PFS) Within 12 Months

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    End point title
    		 Progression–Free Survival (PFS) Within 12 Months
    End point description
    PFS was defined as the time from the date of treatment start to the date of the first documented disease progression or death due to any cause within the first 12 months of treatment. If a subject had not progressed or died after 12 months of treatment or when any further anti-neoplastic therapy was received, PFS was censored at the time of the last tumour assessment before the analysis cut-off date or the anti-neoplastic therapy date. A Kaplan-Meier estimate of the PFS was calculated to determine the number of subjects at risk. Median PFS time (50% of subjects who would not progress or die) of the ITT population is presented along with 95 % CI.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intention-to-treat (ITT) Population
    Number of subjects analysed
    49 [2]
    Units: months
        number (confidence interval 95%)
    11.1 (8.3 to 999999.9)
    Notes
    [2] - 999999.9 = non calculable
    No statistical analyses for this end point

    Secondary: Time To Response (TtR) Within 12 Months

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    End point title
    		 Time To Response (TtR) Within 12 Months
    End point description
    TtR was defined as the time from the date of treatment start to the date of the first documented objective response (CR or PR) within the first 12 months of treatment (combination and maintenance phases). The Kaplan-Meier method was used to estimate the median TtR and its 95% CI for subjects in the ITT population (50% of subjects were expected to have a CR or PR at this time).
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intention-to-treat (ITT) Population
    Number of subjects analysed
    49 [3]
    Units: months
        number (confidence interval 95%)
    999999.9 (999999.9 to 999999.9)
    Notes
    [3] - 999999.9 = non calculable
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) Within 12 Months

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    End point title
    		 Duration of Response (DoR) Within 12 Months
    End point description
    The DoR is an estimation of the time from first documented objective response (CR or PR) to the first date of progressive disease (PD) or death due to disease progression for subjects who experienced an objective response within the first 12 months of treatment (combination and maintenance phases). The Kaplan-Meier method was used to estimate the median DoR and its 95% CI for subjects in the ITT population who had an objective response.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intention-to-treat (ITT) Population
    Number of subjects analysed
    6 [4]
    Units: months
        number (confidence interval 95%)
    999999.9 (999999.9 to 999999.9)
    Notes
    [4] - 999999.9 = non calculable
    No statistical analyses for this end point

    Secondary: Biochemical Response Using Chromogranin-A (CgA) Levels After 6 Months

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    End point title
    		 Biochemical Response Using Chromogranin-A (CgA) Levels After 6 Months
    End point description
    Blood samples for CgA blood tumour marker analysis were taken at baseline, weeks 12, 24 and at early withdrawal. The biochemical response after 6 months combination treatment was estimated for subjects with abnormal CgA levels at baseline. Abnormal CgA levels were defined as above the upper limit of normal range (≥100 micrograms/litre [mcg/L]). Biochemical response based on CgA levels was categorised as: PR = decrease of CgA ≥ 50%, compared to the baseline CgA SD = decrease < 50 % or an increase ≤25%, compared to the baseline CgA PD = defined as an increase ≥25 %, compared to the baseline CgA The number of subjects in each response category at each time point in the combination phase is presented. Analysis was only carried out on subjects in the ITT population who had abnormal CgA at baseline.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Combination Phase
    Number of subjects analysed
    34
    Units: subjects
        Week 12 - PD
    8
        Week 12 - SD
    15
        Week 12 - PR
    10
        Week 12 - Missing
    1
        Week 24 - PD
    5
        Week 24 - SD
    9
        Week 24 - PR
    7
        Week 24 - Missing
    0
        Early Withdrawal - PD
    1
        Early Withdrawal - SD
    2
        Early Withdrawal - PR
    1
        Early Withdrawal - Missing
    14
    No statistical analyses for this end point

    Secondary: Biochemical Response using CgA Levels After 12 Months

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    End point title
    		 Biochemical Response using CgA Levels After 12 Months
    End point description
    Blood samples for CgA blood tumour marker analysis were taken at baseline, weeks 24, 36, 48 (end of study) and at early withdrawal. The biochemical response after 12 months combination and maintenance treatment was estimated for subjects with abnormal CgA levels at baseline. Abnormal CgA levels were defined as above the upper limit of normal range (≥100 mcg/L). Biochemical response based on CgA levels was categorised as: PR = decrease of CgA ≥ 50%, compared to the baseline CgA SD = decrease < 50% or an increase ≤ 25%, compared to the baseline CgA PD = defined as an increase ≥ 25%, compared to the baseline CgA The number of subjects in each response category at each time point in the maintenance phase is presented. Analysis was only carried out on subjects in the ITT population who had abnormal CgA at baseline.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Maintenance Phase - Functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, No Treatment
    Number of subjects analysed
    5
    9
    9
    Units: subjects
        Week 24 - PD
    2
    1
    2
        Week 24 - SD
    3
    4
    2
        Week 24 - PR
    0
    3
    3
        Week 24 - Missing
    0
    1
    2
        Week 36 - PD
    1
    1
    3
        Week 36 - SD
    2
    4
    2
        Week 36 - PR
    0
    1
    4
        Week 36 - Missing
    0
    1
    0
        Week 48 - PD
    1
    1
    2
        Week 48 - SD
    0
    2
    3
        Week 48 - PR
    1
    2
    1
        Week 48 - Missing
    0
    0
    0
        Early Withdrawal - PD
    1
    2
    1
        Early Withdrawal - SD
    0
    0
    0
        Early Withdrawal - PR
    0
    1
    1
        Early Withdrawal - Missing
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Biochemical Response using 5-Hydroxy-Indol-Amino-Acid (5-HIAA) Levels After 6 Months

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    End point title
    		 Biochemical Response using 5-Hydroxy-Indol-Amino-Acid (5-HIAA) Levels After 6 Months
    End point description
    Urine samples for 5-HIAA urinary tumour marker analysis were taken at at baseline, weeks 12, 24 and early withdrawal. Biochemical response based on 5-HIAA levels was categorised as: Response = 5-HIAA reduction compared to baseline Progression = 5-HIAA increase compared to baseline The number of subjects in each response category at each time point in the combination phase is presented. Analysis was only carried out on subjects in the ITT population with functioning NET.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Combination Phase - Functioning NET
    Number of subjects analysed
    17
    Units: subjects
        Week 12 - Progression
    4
        Week 12 - Response
    6
        Week 12 - Not evaulable
    1
        Week 12 - Missing
    6
        Week 24 - Progression
    6
        Week 24 - Response
    3
        Week 24 - Not evaluable
    1
        Week 24 - Missing
    3
        Early Withdrawal - Progression
    0
        Early Withdrawal - Response
    1
        Early Withdrawal - Not Evaluable
    0
        Early Withdrawal - Missing
    7
    No statistical analyses for this end point

    Secondary: Biochemical Response using 5-HIAA Levels After 12 Months

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    End point title
    		 Biochemical Response using 5-HIAA Levels After 12 Months
    End point description
    Urine samples for 5-HIAA a urinary tumour marker analysis were taken at baseline, weeks 12, 24, 36, 48 (end of study) and early withdrawal. Biochemical response based on 5-HIAA levels was categorised as: Response = 5-HIAA reduction compared to baseline Progression = 5-HIAA increase compared to baseline The number of subjects in each response category at each time point in the maintenance phase is presented. Analysis was only carried out on subjects in the ITT population with functioning NET.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Maintenance Phase - Functioning NET, Lanreotide
    Number of subjects analysed
    11
    Units: subjects
        Week 24 - Progression
    6
        Week 24 - Response
    3
        Week 24 - Not evaluable
    1
        Week 24 - Missing
    1
        Week 36 - Progression
    3
        Week 36 - Response
    3
        Week 36 - Not evaluable
    0
        Week 36 - Missing
    3
        Week 48 - Progression
    4
        Week 48 - Response
    2
        Week 48 - Not evaluable
    0
        Week 48 - Missing
    2
        Early Withdrawal - Progression
    0
        Early Withdrawal - Response
    0
        Early Withdrawal - Not evaluable
    0
        Early Withdrawal - Missing
    3
    No statistical analyses for this end point

    Secondary: Symptomatic Response After 6 Months

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    End point title
    		 Symptomatic Response After 6 Months
    End point description
    Symptomatic response was evaluated as absolute change from baseline in the number of episodes of the lead symptoms (i.e. diarrhoea and flushing) using the mean of the last 3 days before the visit, at each visit, as compared to baseline. Symptomatic responses were categorised as: Reduction, Increase or Stability of occurrences of diarrhoea Reduction, Increase or Stability of occurrences of flushing The number of subjects in each response category at week 24 (end of the combination phase) is presented. Analysis was only carried out on subjects in the ITT population with functioning NET.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Combination Phase - Functioning NET
    Number of subjects analysed
    17
    Units: subjects
        Diarrhoea - Reduction
    4
        Diarrhoea - Increase
    2
        Diarrhoea - Stability
    5
        Diarrhoea - Missing
    6
        Flushing - Reduction
    4
        Flushing - Increase
    4
        Flushing - Stability
    3
        Flushing - Missing
    6
    No statistical analyses for this end point

    Secondary: Symptomatic Response After 12 Months

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    End point title
    		 Symptomatic Response After 12 Months
    End point description
    Symptomatic response was evaluated as absolute change from baseline in the number of episodes of the lead symptoms (i.e. diarrhoea and flushing) using the mean of the last 3 days before the visit, at each visit, as compared to baseline. Symptomatic responses were categorised as: Reduction, Increase or Stability of occurrences of diarrhoea Reduction, Increase or Stability of occurrences of flushing The number of subjects in each response category at week 48 (end of study) is presented. Analysis was only carried out on subjects in the ITT population with functioning NET.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Maintenance Phase - Functioning NET, Lanreotide
    Number of subjects analysed
    11
    Units: subjects
        Diarrhoea - Reduction
    4
        Diarrhoea - Increase
    1
        Diarrhoea - Stability
    3
        Diarrhoea - Missing
    3
        Flushing - Reduction
    2
        Flushing - Increase
    3
        Flushing - Stability
    3
        Flushing - Missing
    3
    No statistical analyses for this end point

    Secondary: Quality of Life (QoL) Core 30 Questionnaire (QLQ-C30): Mean Change from Baseline at 6 Months

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    End point title
    		 Quality of Life (QoL) Core 30 Questionnaire (QLQ-C30): Mean Change from Baseline at 6 Months
    End point description
    Subjects were instructed to complete the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire at baseline, weeks 12, 24 or at early withdrawal. The QLQ-C30 questionnaire contains 30 single items (Q1 – Q30). Q1 –Q28 scores range from 1 to 4 with 1 being the most favourable answer and 4 the worst case (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much). Q29 and Q30 scores range from 1 (= Very poor) to 7 (= Excellent) with 1 being the worst case and 7 the most favourable answer. Subscores from the 5 functional scales, 3 symptom scales, a global health status/QoL scale, and 6 single items were derived according to the rules contained within the EORTC Scoring Manual. The mean change from baseline at week 24 (end of the combination phase) is presented for each of the category subscores. Only subjects with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Combination Phase
    Number of subjects analysed
    34 [5]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Global health status
    -4.9 ± 18.2
        Physical functioning
    -9.6 ± 19.4
        Role functioning
    -8.3 ± 27.6
        Emotional functioning
    -4.7 ± 17.7
        Cognitive functioning
    -5.9 ± 15.8
        Social functioning
    -11.8 ± 23.8
        Fatigue
    6.9 ± 20.1
        Nausea and vomiting
    6.9 ± 14.9
        Pain
    -1.0 ± 31.0
        Dyspnoea
    12.7 ± 30.7
        Insomnia
    0.0 ± 34.9
        Appetite loss
    2.0 ± 24.5
        Constipation
    6.9 ± 33.6
        Diarrhoea
    -3.9 ± 34.6
        Financial difficulties
    2.9 ± 17.1
    Notes
    [5] - Insomnia (n=32)
    No statistical analyses for this end point

    Secondary: QoL Questionnaire QLQ-C30: Mean Change from Baseline at 12 Months

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    End point title
    		 QoL Questionnaire QLQ-C30: Mean Change from Baseline at 12 Months
    End point description
    Subjects were instructed to complete the EORTC QLQ-C30 questionnaire at baseline, weeks 12, 24, 36, 48 (end of study) or at early withdrawal. The QLQ-C30 questionnaire contains 30 single items (Q1 – Q30). Q1 –Q28 scores range from 1 to 4 with 1 being the most favourable answer and 4 the worst case (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much). Q29 and Q30 scores range from 1 (= Very poor) to 7 (= Excellent) with 1 being the worst case and 7 the most favourable answer. Subscores from the 5 functional scales, 3 symptom scales, a global health status/QoL scale, and 6 single items were derived according to the rules contained within the EORTC Scoring Manual. The mean change from baseline at week 48 (end of study) is presented for each of the category subscores. Only subjects with data available for analysis are presented for each arm.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Maintenance Phase - Functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, No Treatment
    Number of subjects analysed
    5 [6]
    8
    7 [7]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Global health status
    -11.7 ± 40.7
    -3.1 ± 10.9
    -7.1 ± 15.5
        Physical functioning
    8.0 ± 22.8
    -12.5 ± 17.6
    -11.4 ± 13.7
        Role functioning
    3.3 ± 29.8
    -2.1 ± 20.8
    -7.1 ± 13.1
        Emotional functioning
    15.0 ± 19.0
    -6.2 ± 20.3
    -6.0 ± 12.5
        Cognitive functioning
    3.3 ± 24.7
    -2.1 ± 20.8
    2.4 ± 6.3
        Social functioning
    13.3 ± 34.2
    -22.9 ± 34.4
    -4.8 ± 15.9
        Fatigue
    -22.2 ± 30.4
    9.7 ± 24.1
    4.8 ± 16.8
        Nausea and vomiting
    -10.0 ± 14.9
    4.2 ± 23.1
    2.4 ± 6.3
        Pain
    -13.3 ± 32.1
    4.2 ± 24.8
    9.5 ± 23.3
        Dyspnoea
    -8.3 ± 41.9
    4.2 ± 33.0
    9.5 ± 16.3
        Insomnia
    -13.3 ± 50.6
    -8.3 ± 34.5
    16.7 ± 27.9
        Appetite loss
    0.0 ± 23.6
    0.0 ± 39.8
    14.3 ± 17.8
        Constipation
    20.0 ± 38.0
    -4.2 ± 11.8
    -4.8 ± 35.6
        Diarrhoea
    -40.0 ± 36.5
    8.3 ± 15.4
    0.0 ± 27.2
        Financial difficulties
    6.7 ± 14.9
    4.2 ± 27.8
    9.5 ± 25.2
    Notes
    [6] - Dyspnoea (n=4)
    [7] - Insomnia (n=6)
    No statistical analyses for this end point

    Secondary: Quality of Life Gastrointestinal Neuroendocrine Tumour 21 Questionnaire (QLQ-GI.NET21): Mean Change from Baseline at 6 Months

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    End point title
    		 Quality of Life Gastrointestinal Neuroendocrine Tumour 21 Questionnaire (QLQ-GI.NET21): Mean Change from Baseline at 6 Months
    End point description
    Subjects were instructed to complete the QLQ-GI.NET21 questionnaire at baseline, weeks 12, 24 or at early withdrawal. The QLQ-G.I.NET21 questionnaire contains 21 single items (Q31 – Q51) which are supplemental items to the EORTC QLQ-C30 questionnaire. Q31 – Q51 scores range from 1 to 4 with 1 being the most favourable answer and 4 the worst case (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much). Based on these items the subscores were generated. The mean change from baseline at 6 months (week 24) is presented for each of the category subscores. Only subjects with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Combination Phase
    Number of subjects analysed
    34 [8]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Endocrine symptoms
    -1.0 ± 13.5
        Gastrointestinal (G.I.) symptoms
    5.7 ± 14.0
        Treatment related symptoms
    3.6 ± 30.1
        Social function
    2.3 ± 25.3
        Disease related worries
    1.6 ± 27.1
        Muscle/bone pain symptoms
    1.0 ± 37.1
        Body image
    0.0 ± 23.2
        Weight gain
    -11.8 ± 30.5
        Information/communication (Info/com) function
    -9.4 ± 22.8
        Sexual function
    -4.8 ± 17.8
    Notes
    [8] - Treatment related symptoms (n=14) Weight gain (n=31) Info/com function (n=32) Sexual function (n=14)
    No statistical analyses for this end point

    Secondary: QoL questionnaire QLQ-GI.NET21: Mean Change from Baseline at 12 Months

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    End point title
    		 QoL questionnaire QLQ-GI.NET21: Mean Change from Baseline at 12 Months
    End point description
    Subjects were instructed to complete the QLQ-GI.NET21 questionnaire at baseline, weeks 12, 24, 36, 48 (end of study) or at early withdrawal. The QLQ-G.I.NET21 questionnaire contains 21 single items (Q31 – Q51) which are supplemental items to the EORTC QLQ-C30 questionnaire. Q31 – Q51 scores range from 1 to 4 with 1 being the most favourable answer and 4 the worst case (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much). Based on these items the subscores were generated. The mean change from baseline at 12 months (week 48) is presented for each of the category subscores.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Maintenance Phase - Functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, No Treatment
    Number of subjects analysed
    5 [9]
    8 [10]
    7 [11]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Endocrine symptoms
    -13.3 ± 21.4
    -5.6 ± 19.7
    1.6 ± 4.2
        G.I. symptoms
    -4.0 ± 21.9
    0.0 ± 19.2
    6.7 ± 7.7
        Treatment related symptoms
    0.0 ± 0.0
    -11.1 ± 34.7
    999999.9 ± 999999.9
        Social function
    -6.7 ± 23.0
    9.7 ± 20.9
    -6.3 ± 16.8
        Disease related worries
    -6.7 ± 36.5
    1.4 ± 15.1
    -3.2 ± 30.6
        Muscle/bone pain symptoms
    -6.7 ± 14.9
    4.2 ± 33.0
    4.8 ± 30.0
        Body image
    0.0 ± 23.6
    4.2 ± 27.8
    4.8 ± 12.6
        Weight gain
    -20.0 ± 29.8
    9.5 ± 25.2
    -9.5 ± 56.8
        Information/communication function
    0.0 ± 70.7
    0.0 ± 17.8
    -4.8 ± 12.6
        Sexual function
    0.0 ± 0.0
    0.0 ± 0.0
    0.0 ± 0.0
    Notes
    [9] - Treatment related symptoms (n=2) Sexual function (n=2)
    [10] - Treatment related symptoms (n=3) Weight gain (n=7) Sexual function (n=4)
    [11] - Treatment related symptoms (n=0) Sexual function (n=3) 999999.9 = non calculable
    No statistical analyses for this end point

    Secondary: DCR by O6-methylguanine-DNA methyl-transferase (MGMT) Expression and Methylation and Somatostatin Receptor (SSTR) Expression After 6 Months

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    End point title
    		 DCR by O6-methylguanine-DNA methyl-transferase (MGMT) Expression and Methylation and Somatostatin Receptor (SSTR) Expression After 6 Months
    End point description
    In all subjects whose tumour tissue was available, MGMT expression/methylation and SSTR expression was analysed. After 6 months, the DCR (SD+PR+CR) by MGMT methylation and expression and by SSTR 2a and SSTR 5 expression was evaluated. DCR in response to MGMT methylation and expression results are presented. SSTR 2a and SSTR 5 expression is categorised as: No Receptors, Cytoplasmatic Expression (CE), Focal Expression (FE), Complete Circumferent Membrane Expression (CCME). The DCR was defined as the proportion of subjects with a response of CR, PR or SD after 6 months of combination treatment within each methylation/expression category. The DCR was described in the ITT population along with its 95% CI and was compared to 45% with an exact binomial proportion test. Only subjects with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Combination Phase
    Number of subjects analysed
    49
    Units: percentage of subjects
    number (confidence interval 95%)
        MGMT Methylation (n=9)
    100 (66.4 to 100)
        MGMT No methylation (n=13)
    84.6 (54.6 to 98.1)
        MGMT Expression (n=11)
    90.9 (58.7 to 99.8)
        MGMT No expression (n=20)
    70.0 (45.7 to 88.1)
        SSTR 2a No Receptors (n=0)
    9999999.9 (9999999.9 to 9999999.9)
        SSTR 2a CE (n=0)
    9999999.9 (9999999.9 to 9999999.9)
        SSTR 2a FE (n=15)
    86.7 (59.5 to 98.3)
        SSTR 2a CCME (n=22)
    72.7 (49.8 to 89.3)
        SSTR 5 - No Receptors (n=24)
    75.0 (53.3 to 90.2)
        SSTR 5 CE (n=2)
    100.0 (15.8 to 100.0)
        SSTR 5 FE (n=11)
    81.8 (48.2 to 97.7)
        SSTR 5 CCME (n=0)
    9999999.9 (9999999.9 to 9999999.9)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Results: Lanreotide ATG 120 mg Serum After 12 Months

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    End point title
    		 Pharmacokinetic (PK) Results: Lanreotide ATG 120 mg Serum After 12 Months
    End point description
    Lanreotide ATG levels were measured in a subset of subjects to evaluate if temozolomide co-treatment had an impact on lanreotide serum concentration over a 12 month period. Blood samples were collected for the determination of lanreotide ATG in serum at baseline, weeks 12, 24 and 48 (end of study). The concentrations of lanreotide ATG in serum were determined by a validated radioimmunoassay analysis method with a lower limit of quantitation of 0.08 nanograms [ng]/mL). Serum concentrations of lanreotide ATG at each of the time points in the combination and maintenance phase are presented. Only subjects with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Pharmacokinetic (PK) Subset
    Number of subjects analysed
    16
    Units: Nanograms (ng)/mL
    arithmetic mean (standard deviation)
        Baseline
    0.44 ± 1.22
        Week 4 (n=14)
    2.45 ± 1.16
        Week 12 (n=11)
    5.06 ± 3.01
        Week 24 (n=9)
    1.93 ± 6.13
        Week 48 (n=7)
    3.68 ± 3.36
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    13 months (12 month study treatment plus 28 days)
    Adverse event reporting additional description
    Treatment Emergent Adverse Events (TEAEs) are reported for both the combination and maintenance phases and include events with an onset after the start of study drug treatment to the last intake of study drug plus 28 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Combination Phase
    Reporting group description
    		 All subjects received lanreotide ATG 120 mg plus temozolomide in combination for 6 months. Subjects received one injection of lanreotide ATG 120 mg and temozolomide capsules for 5 consecutive days, in a 28 days treatment cycle . The temozolomide dose was adapted to the subject BSA, and the dose in the 1st treatment cycle was 150 mg/m^2 per day. Depending on the safety laboratory values, the temozolomide dose was increased to 200 mg/m^2 per day from cycle 2 to cycle 6.

    Reporting group title
    Maintenance Phase - Functioning NET, Lanreotide
    Reporting group description
    		 In case of clinical benefit, defined as either CR, PR or SD after the first 6 months combination phase, all subjects with functioning (serotonin producing) NET continued to receive lanreotide ATG 120 mg for another 6 months. This maintenance phase started with visit 8, week 24.

    Reporting group title
    Maintenance Phase - Non-functioning NET, Lanreotide
    Reporting group description
    		 Following completion of the 6-month combination phase, all subjects with non-functioning NET and clinical benefit were randomised to continue to receive lanreotide ATG 120 mg for another 6 months. This maintenance phase started with visit 8, week 24.

    Reporting group title
    Maintenance Phase - Non-functioning NET, No Treatment
    Reporting group description
    		 Following completion of the 6-month combination phase, all subjects with non-functioning NET and clinical benefit were randomised to receive no treatment for 6 months. This maintenance phase started with visit 8, week 24.

    Serious adverse events
    		 Combination Phase Maintenance Phase - Functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, No Treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 57 (29.82%)
    3 / 11 (27.27%)
    4 / 14 (28.57%)
    4 / 12 (33.33%)
         number of deaths (all causes)
    1
    1
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to gastrointestinal tract
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Penile squamous cell carcinoma
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Ocular vascular disorder
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seronegative arthritis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Combination Phase Maintenance Phase - Functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, Lanreotide Maintenance Phase - Non-functioning NET, No Treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 57 (91.23%)
    9 / 11 (81.82%)
    13 / 14 (92.86%)
    11 / 12 (91.67%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    0
    1
    Neoplasm progression
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Tumour pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Haematoma
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    5
    3
    0
    0
    Hypertension
         subjects affected / exposed
    5 / 57 (8.77%)
    1 / 11 (9.09%)
    2 / 14 (14.29%)
    2 / 12 (16.67%)
         occurrences all number
    5
    1
    2
    2
    Lymphoedema
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    General disorders and administration site conditions
    Administration site extravasation
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Asthenia
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 11 (9.09%)
    2 / 14 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    2
    1
    Chest discomfort
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Fatigue
         subjects affected / exposed
    19 / 57 (33.33%)
    2 / 11 (18.18%)
    4 / 14 (28.57%)
    5 / 12 (41.67%)
         occurrences all number
    32
    2
    4
    7
    Feeling cold
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    0
    1
    General physical health deterioration
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Injection site pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    4 / 57 (7.02%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    2 / 12 (16.67%)
         occurrences all number
    4
    0
    1
    2
    Pain
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    4 / 57 (7.02%)
    1 / 11 (9.09%)
    3 / 14 (21.43%)
    3 / 12 (25.00%)
         occurrences all number
    5
    1
    4
    8
    Thirst
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    6
    0
    1
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    1
    Pleural effusion
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Disorientation
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 11 (0.00%)
    2 / 14 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    2
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    0
    2
    Blood creatinine increased
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    1
    1
    Blood uric acid increased
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    4
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 57 (10.53%)
    1 / 11 (9.09%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    6
    2
    1
    1
    Liver function test abnormal
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Red blood cell count decreased
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    8 / 57 (14.04%)
    0 / 11 (0.00%)
    2 / 14 (14.29%)
    3 / 12 (25.00%)
         occurrences all number
    8
    0
    2
    3
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Atrial thrombosis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Atrioventricular block
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bradycardia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Cardiac failure
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    0
    1
    Diastolic dysfunction
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Tricuspid valve incompetence
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    2 / 14 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    2
    1
    Nervous system disorders
    Carotid arteriosclerosis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Disturbance in attention
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Dizziness
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    6
    0
    0
    2
    Dysgeusia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    3 / 14 (21.43%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Headache
         subjects affected / exposed
    7 / 57 (12.28%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    9
    1
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Polyneuropathy
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Tremor
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 57 (12.28%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    9
    0
    0
    3
    Coagulopathy
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Leukocytosis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    1
    1
    Leukopenia
         subjects affected / exposed
    6 / 57 (10.53%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    8
    0
    0
    3
    Lymphadenopathy
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Lymphopenia
         subjects affected / exposed
    8 / 57 (14.04%)
    0 / 11 (0.00%)
    2 / 14 (14.29%)
    4 / 12 (33.33%)
         occurrences all number
    10
    0
    2
    8
    Neutropenia
         subjects affected / exposed
    6 / 57 (10.53%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    7
    1
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    16 / 57 (28.07%)
    1 / 11 (9.09%)
    3 / 14 (21.43%)
    0 / 12 (0.00%)
         occurrences all number
    28
    1
    3
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Vertigo
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    6
    0
    0
    1
    Eye disorders
    Ocular vascular disorder
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Photopsia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    4 / 57 (7.02%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    7
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    12 / 57 (21.05%)
    2 / 11 (18.18%)
    4 / 14 (28.57%)
    2 / 12 (16.67%)
         occurrences all number
    22
    3
    6
    2
    Anal inflammation
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Ascites
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Constipation
         subjects affected / exposed
    11 / 57 (19.30%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    16
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    21 / 57 (36.84%)
    0 / 11 (0.00%)
    3 / 14 (21.43%)
    2 / 12 (16.67%)
         occurrences all number
    35
    0
    4
    2
    Dyspepsia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Eructation
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Faecal incontinence
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Flatulence
         subjects affected / exposed
    10 / 57 (17.54%)
    1 / 11 (9.09%)
    2 / 14 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    16
    1
    3
    1
    Frequent bowel movements
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    1
    Intestinal ischaemia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Lip dry
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Melaena
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    24 / 57 (42.11%)
    1 / 11 (9.09%)
    4 / 14 (28.57%)
    1 / 12 (8.33%)
         occurrences all number
    55
    1
    5
    1
    Pancreatic insufficiency
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Steatorrhoea
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vomiting
         subjects affected / exposed
    19 / 57 (33.33%)
    1 / 11 (9.09%)
    2 / 14 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    40
    1
    3
    1
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Hepatic pain
         subjects affected / exposed
    3 / 57 (5.26%)
    2 / 11 (18.18%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    2
    0
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Pruritus
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 11 (9.09%)
    2 / 14 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    2
    0
    Rash
         subjects affected / exposed
    5 / 57 (8.77%)
    2 / 11 (18.18%)
    2 / 14 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    6
    2
    2
    1
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 11 (9.09%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 57 (8.77%)
    1 / 11 (9.09%)
    2 / 14 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    9
    1
    2
    1
    Back pain
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    1
    2
    Joint swelling
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Muscle tightness
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    0
    1
    Synovial cyst
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    7 / 57 (12.28%)
    3 / 11 (27.27%)
    2 / 14 (14.29%)
    3 / 12 (25.00%)
         occurrences all number
    8
    4
    3
    3
    Otitis media
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 11 (9.09%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    1
    Decreased appetite
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Dehydration
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Diabetes mellitus
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Glucose tolerance impaired
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    0
    2
    Hyperkalaemia
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    2 / 14 (14.29%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    2
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    0
    4
    Hypocalcaemia
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    1
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jun 2014
    This amendment included 1 addition to inclusion criteria and 1 addition to exclusion criteria and to reference the results of the previous CLARINET study. Minor changes and clarifications concerning stopping rules and discontinuation criteria, the secondary efficacy criterion (DCR) and the choice of methods for tumour assessment were also added.
    06 Nov 2014
    This amendment included an update of the synopsis, the Schedule of Assessment table and the addition of a section “Reporting Exemptions'. Clarifications were also added concerning the baseline visit, the providing of capsules of temozolomide (bottles or blisters), haematology tests, concomitant medications or therapies not permitted during the study, the reference documents for assessment of expected adverse events (AEs) and Data Safety Monitoring Committee.
    24 Nov 2015
    This amendment included an increase in number of screened subjects (total number of evaluable subjects unchanged), an update of the Schedule of Assessment and other administrative changes. Clarifications concerning the follow-up visit, CT/MRI scan, laboratory assessment related to temozolodine dosing and dose adjustment, report of Serious AE related to temozolodine and the interim analysis were also included.

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

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