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    Clinical Trial Results:
    EFFICACY AND SAFETY OF LANREOTIDE ATG 120 MG IN COMBINATION WITH TMZ IN SUBJECTS WITH PROGRESSIVE WELL DIFFERENTIATED THORACIC NEUROENDOCRINE TUMOURS

    Summary
    EudraCT number
    		 2014-005579-10
    Trial protocol
    		 IT  
    Global end of trial date
    18 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Aug 2020
    First version publication date
    20 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A-93-52030-325
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02698410
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ipsen SpA
    Sponsor organisation address
    Via del Bosco Rinnovato n. 6, Milanofiori Nord - Palazzo U7, Assago, Italy, 20090
    Public contact
    Medical Director, Ipsen SpA, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Ipsen SpA, 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
    18 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of lanreotide autogel (ATG) 120 milligrams (mg) in combination with temozolomide (TMZ) in participants with unresectable advanced neuroendocrine tumours (NET) of the lung (typical and atypical carcinoids according to the WHO 2004 criteria) or thymus as disease control rate (DCR), defined as complete response (CR), partial response (PR) and stable disease (SD) at 9 months, according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria v 1.1.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki (version 2013), in accordance with the International Conference on Harmonisation Consolidated Guideline on Good Clinical Practice and in compliance with independent ethics committees and informed consent regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jul 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    14
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This pilot study was conducted at 11 investigational sites in Italy between 06 July 2016 and 18 June 2019.

    Pre-assignment
    Screening details
    		 The study consisted of a screening period (maximum 4 weeks), followed by an open label treatment period of up to a maximum of 52 weeks or until disease progression, death or unacceptable toxicity, or subject/physician decision.

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

    Arms
    Arm title
    		 Lanreotide ATG plus Temozolomide
    Arm description
    		 Lanreotide ATG 120 mg was administered by deep subcutaneous injection on Day 1 (baseline) and every 28 days for up to 52 weeks. Participants also received temozolomide 250 mg capsule orally once daily for 5 consecutive days every 28 days for up to 52 weeks. The dose of temozolomide could subsequently be reduced to 180 mg daily for 5 consecutive days every 28 days in case of bone marrow toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A dose of lanreotide ATG 120 mg was provided in a pre-filled syringe at baseline and every 28 days for a maximum of 48 weeks of treatment (total number of 13 injections), and a maximum delay of 4 weeks in lanreotide administration was allowed.

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    A starting dose of temozolomide 250 mg/day was administered in the fasting state for 5 consecutive days every 28 days for a maximum of 48 weeks or until progression/death or toxicity. In case of bone marrow toxicity the dose could subsequently be reduced to 180 mg daily for 5 consecutive days of each month.

    Number of subjects in period 1
    		Lanreotide ATG plus Temozolomide
    Started
    40
    Completed
    36
    Not completed
    4
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    2
         Unspecified
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lanreotide ATG plus Temozolomide
    Reporting group description
    		 Lanreotide ATG 120 mg was administered by deep subcutaneous injection on Day 1 (baseline) and every 28 days for up to 52 weeks. Participants also received temozolomide 250 mg capsule orally once daily for 5 consecutive days every 28 days for up to 52 weeks. The dose of temozolomide could subsequently be reduced to 180 mg daily for 5 consecutive days every 28 days in case of bone marrow toxicity.

    Reporting group values
    		 Lanreotide ATG plus Temozolomide Total
    Number of subjects
    		 40 40
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.9 ( 11.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 16
        Male
    		 24 24
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 40 40
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    Lanreotide ATG plus Temozolomide
    Reporting group description
    		 Lanreotide ATG 120 mg was administered by deep subcutaneous injection on Day 1 (baseline) and every 28 days for up to 52 weeks. Participants also received temozolomide 250 mg capsule orally once daily for 5 consecutive days every 28 days for up to 52 weeks. The dose of temozolomide could subsequently be reduced to 180 mg daily for 5 consecutive days every 28 days in case of bone marrow toxicity.

    Primary: DCR Assessed Locally at Month 9

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    End point title
    		 DCR Assessed Locally at Month 9 [1]
    End point description
    Responders were participants who showed disease control according to RECIST criteria v 1.1 assessed locally by the investigator. DCR was defined as CR, PR or SD according to RECIST criteria v1.1. A sensitivity analysis-1 of local DCR was performed excluding participants withdrawn before 9 months with reason other than progressive disease (PD) or missing assessment and considering participants with PD prior or at 9 months as failures. A sensitivity analysis-2 was performed to consider assessments done between 7.5 and 10.5 months as 9 months assessments when 9-month assessment was missing using same methodology of sensitivity analysis-1. P-value for DCR to 30% and 10% clinically relevant threshold was 0.2968 and <0.0001, respectively. P-value for sensitivity analysis-1 DCR to 30% and 10% clinically relevant threshold was 0.0534 and <0.0001, respectively. P-value for sensitivity analysis-2 DCR to 30% and 10% clinically relevant threshold was 0.032 and <0.0001, respectively.
    End point type
    Primary
    End point timeframe
    Up to Month 9; for sensitivity analysis-2, up to 10.5 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 data is presented for a single reporting arm, the analysis of the comparison of DCR to the clinically relevant threshold of 30% and 10% is reported within the end point description.
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40 [2]
    Units: percentage of participants
    number (confidence interval 95%)
        DCR at Month 9 (n=40)
    35.0 (20.63 to 51.68)
        Sensitivity analysis-1 (n=31)
    45.2 (27.32 to 63.97)
        Sensitivity analysis-2 (n=40)
    45.0 (29.26 to 61.51)
    Notes
    [2] - The ITT/Safety population. Here, n = number of participants analysed for each time point.
    No statistical analyses for this end point

    Secondary: DCR Assessed Centrally at Month 9

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    End point title
    		 DCR Assessed Centrally at Month 9
    End point description
    The DCR was defined as SD, PR or CR according to RECIST criteria v1.1. A second set of the original computed tomography (CT) scan images were used for a centralized RECIST v1.1 assessment by an independent radiologist. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
    End point type
    Secondary
    End point timeframe
    Up to Month 9
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40
    Units: percentage of participants
        number (confidence interval 95%)
    28.2 (15.00 to 44.87)
    No statistical analyses for this end point

    Secondary: Median Progression Free Survival (PFS) Assessed Locally and Centrally

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    End point title
    		 Median Progression Free Survival (PFS) Assessed Locally and Centrally
    End point description
    The PFS was defined as the time from the first treatment administration to disease progression according to RECIST criteria v 1.1 or death from any cause. The PFS was assessed locally by the investigator and centrally by an independent radiologist. The distribution of PFS times was estimated using the Kaplan-Meier method. The PFS of participants who were lost to follow-up and those who had not progressed at end of study were censored at the date of the last disease assessment. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
    End point type
    Secondary
    End point timeframe
    From Day 1 up to end of study, 52 weeks
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40
    Units: weeks
    median (confidence interval 95%)
        Local assessment
    37.1 (24.1 to 52.9)
        Central assessment
    37.1 (24.1 to 56.0)
    No statistical analyses for this end point

    Secondary: Median Time to Response (TTR) Assessed Locally and Centrally

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    End point title
    		 Median Time to Response (TTR) Assessed Locally and Centrally
    End point description
    The TTR was defined as the time from first treatment administration to the first objective tumour response (PR or CR according to RECIST criteria v 1.1). The TTR was assessed locally by the investigator and centrally by an independent radiologist. The distribution of TTR was estimated using the Kaplan-Meier method. The TTR of participants who were lost to follow-up or died prior to any objective tumour response were censored at the date of the last disease assessment. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide). -9999 and 9999 = Not computed as the median TTR could not be estimated due to the low number of participants with an objective response (OR).
    End point type
    Secondary
    End point timeframe
    From Day 1 up to end of study, 52 weeks
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40
    Units: weeks
    median (confidence interval 95%)
        Local assessment
    9999 (-9999 to 9999)
        Central assessment
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Median Duration of Response (DOR) Assessed Locally and Centrally

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    End point title
    		 Median Duration of Response (DOR) Assessed Locally and Centrally
    End point description
    The DOR was defined as the time from onset of the first objective tumour response (PR or CR) to objective tumour progression (PD) according to RECIST criteria v 1.1. The DOR was assessed locally by the investigator and centrally by an independent radiologist. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide). -9999 and 9999 = The median DOR could not be estimated due to the low number of participants with an OR with no documented PD.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to end of study, 52 weeks
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40
    Units: weeks
    median (confidence interval 95%)
        Local assessment
    9999 (-9999 to 9999)
        Central assessment
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Median Time to Progression (TTP) Assessed Locally and Centrally

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    End point title
    		 Median Time to Progression (TTP) Assessed Locally and Centrally
    End point description
    The TTP was defined as the time from first treatment administration to the first objective tumour progression (PD) according to RECIST criteria v 1.1. The TTP was assessed locally by the investigator and centrally by an independent radiologist. The distribution of TTP times was estimated using the Kaplan-Meier method. The TTP of participants who were lost to follow-up, and those who had not progressed at end of study were censored at the date of the last disease assessment. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
    End point type
    Secondary
    End point timeframe
    From Day 1 up to end of study, 52 weeks
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40
    Units: weeks
    median (confidence interval 95%)
        Local assessment
    37.1 (26.4 to 55.1)
        Central assessment
    37.1 (24.1 to 56.0)
    No statistical analyses for this end point

    Secondary: Best Overall Response (BOR) Assessed Locally and Centrally

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    End point title
    		 Best Overall Response (BOR) Assessed Locally and Centrally
    End point description
    The BOR was defined as the highest OR achieved by the participant from the time of first treatment until disease progression/recurrence or the end of study according to RECIST criteria v1.1 and was classified as: CR > PR > Non-CR/Non-progressive disease (NCR/NPD) > SD > PD > ND > not evaluable (NE). The BOR was assessed locally by the investigator and centrally by an independent radiologist. Percentages are based on the number of participants in the ITT/Safety population with non-missing observations. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide). Here, 'n' is defined as number of participants analysed at each assessments.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to end of study, 52 weeks
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40
    Units: percentage of participants
    number (not applicable)
        Local assessment: CR (n=39)
    0
        Local assessment: PR (n=39)
    7.7
        Local assessment: SD (n=39)
    71.8
        Local assessment: NCR/NPD (n=39)
    0
        Local assessment: PD (n=39)
    20.5
        Local assessment: NE (n=39)
    0
        Local assessment: not applicable (n=39)
    0
        Central assessment: CR (n=38)
    0
        Central assessment: PR (n=38)
    13.2
        Central assessment: SD (n=38)
    65.8
        Central assessment: NCR/NPD (n=38)
    2.6
        Central assessment: PD (n=38)
    15.8
        Central assessment: NE (n=38)
    0
        Central assessment: not applicable (n=38)
    2.6
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) Assessed Locally and Centrally at Months 9 and 12

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    End point title
    		 Objective Response Rate (ORR) Assessed Locally and Centrally at Months 9 and 12
    End point description
    The ORR was defined as the percentage of participants with CR or PR according to RECIST criteria v1.1. The ORR was assessed locally by the investigator and centrally by an independent radiologist. The ORR was based on the participants with PD prior to 9 and 12 months with respectively PD at 9 and 12 months, and participants withdrawn before the assessment for reason other than PD or missing as failures. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
    End point type
    Secondary
    End point timeframe
    Months 9 and 12
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40
    Units: percentage of participants
    number (confidence interval 95%)
        Local assessment: Month 9
    2.5 (0.06 to 13.16)
        Local assessment: Month 12
    2.5 (0.06 to 13.16)
        Central assessment: Month 9
    5.1 (0.63 to 17.32)
        Central assessment: Month 12
    2.6 (0.06 to 13.48)
    No statistical analyses for this end point

    Secondary: DCR Assessed Locally and Centrally at Month 12

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    End point title
    		 DCR Assessed Locally and Centrally at Month 12
    End point description
    The DCR was defined as SD, PR or CR according to RECIST criteria v1.1. The DCR was assessed locally by the investigator and centrally by an independent radiologist. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40
    Units: percentage of participants
    number (confidence interval 95%)
        Local assessment
    17.5 (7.34 to 32.78)
        Central assessment
    15.4 (5.86 to 30.53)
    No statistical analyses for this end point

    Secondary: DCR Assessed Locally and Centrally at Month 9 by Carcinoid Type

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    End point title
    		 DCR Assessed Locally and Centrally at Month 9 by Carcinoid Type
    End point description
    The influence of type of carcinoid (typical, atypical and undetermined carcinoid NET) on the local and central DCR at 9 months was analysed. Typical carcinoids were defined with absent foci of necrosis and mitotic count < 2 mitoses/2 millimeters^2 (mm^2); atypical carcinoids were defined with presence of foci of necrosis and/or 2 mitoses/2 mm^2 <= mitotic count <= 10 mitoses/2 mm^2; and carcinoid NET were defined as confirmed carcinoid without foci of necrosis and/or mitotic count reported. The DCR was assessed locally by the investigator and centrally by an independent radiologist. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide). Here, 'n' is defined as number of participants analysed for each carcinoid type. -9999 and 9999 = The confidence interval could not be calculated due to no events.
    End point type
    Secondary
    End point timeframe
    Up to Month 9
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40
    Units: percentage of participants
    number (confidence interval 95%)
        Local: Typical carcinoid (n=8)
    12.5 (0.32 to 52.65)
        Local: Atypical carcinoid (n=21)
    47.6 (25.71 to 70.22)
        Local: Carcinoid NET (n=11)
    27.3 (6.02 to 60.97)
        Central: Typical carcinoid (n=8)
    0 (-9999 to 9999)
        Central: Atypical carcinoid (n=21)
    35.0 (15.39 to 59.22)
        Central: Carcinoid NET (n=11)
    36.4 (10.93 to 69.21)
    No statistical analyses for this end point

    Secondary: Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels

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    End point title
    		 Percentage of Biochemical Responders According to Chromogranin A (CgA) Plasma Levels
    End point description
    Participants with baseline CgA plasma levels greater than the upper limit of normal (ULN) were assessed for a biochemical response. A biochemical responder was defined as a participant who had a decrease of CgA >= 50% compared to baseline, while biochemical SD was defined as a decrease < 50% or an increase <= 25% compared to baseline. Biochemical non-responders had an increase >25% compared to baseline. Baseline was defined as value at Day 1. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide). Only participants with baseline CgA levels greater than ULN were analysed. Here, 'n' is defined as number of participants analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 4, 12, 24, 36 and 52
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    24
    Units: percentage of participants
    number (confidence interval 95%)
        Week 4: Responders (n=22)
    27.3 (9.36 to 45.13)
        Week 4: SD (n=22)
    59.1 (31.31 to 72.2)
        Week 4: Non-responders (n=22)
    13.6 (2.55 to 31.22)
        Week 12: Responders (n=16)
    37.5 (11.89 to 54.28)
        Week 12: SD (n=16)
    37.5 (11.89 to 54.28)
        Week 12: Non-responders (n=16)
    25.0 (5.73 to 43.66)
        Week 24: Responders (n=13)
    23.1 (5.04 to 53.81)
        Week 24: SD (n=13)
    30.8 (9.09 to 61.43)
        Week 24: Non-responders (n=13)
    46.2 (19.22 to 74.87)
        Week 36: Responders (n=11)
    36.4 (9.09 to 61.43)
        Week 36: SD (n=11)
    27.3 (5.04 to 53.81)
        Week 36: Non-responders (n=11)
    36.4 (9.09 to 61.43)
        Week 52: Responders (n=8)
    12.5 (0.28 to 48.25)
        Week 52: SD (n=8)
    50.0 (13.7 to 78.8)
        Week 52: Non-responders (n=8)
    37.5 (7.49 to 70.07)
    No statistical analyses for this end point

    Secondary: Neuron-Specific Enolase (NSE) and CgA Biomarker Levels

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    End point title
    		 Neuron-Specific Enolase (NSE) and CgA Biomarker Levels
    End point description
    The NSE and CgA levels were classified according to ULN as follows: < 1 ULN, 1-2 ULN and > 2 ULN. Baseline was defined as value at Day 1. Percentages are based on the number of participants in the ITT/Safety population who attended the visit with non-missing observations. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide). Here, 'n' is defined as number of participants analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 12, 24, 36 and 52
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40
    Units: percentage of participants
    number (not applicable)
        CgA: Baseline: <1 ULN (n=40)
    40.0
        CgA: Baseline: 1-2 ULN (n=40)
    15.0
        CgA: Baseline: >2 ULN (n=40)
    45.0
        CgA: Week 4: <1 ULN (n=35)
    34.3
        CgA: Week 4: 1-2 ULN (n=35)
    22.9
        CgA: Week 4: >2 ULN (n=35)
    42.9
        CgA: Week 12: <1 ULN (n=28)
    46.4
        CgA: Week 12: 1-2 ULN (n=28)
    17.9
        CgA: Week 12: >2 ULN (n=28)
    35.7
        CgA: Week 24: <1 ULN (n=20)
    30.0
        CgA: Week 24: 1-2 ULN (n=20)
    25.0
        CgA: Week 24: >2 ULN (n=20)
    45.0
        CgA: Week 36: <1 ULN (n=16)
    31.3
        CgA: Week 36: 1-2 ULN (n=16)
    12.5
        CgA: Week 36: >2 ULN (n=16)
    56.3
        CgA: Week 52: <1 ULN (n=11)
    27.3
        CgA: Week 52: 1-2 ULN (n=11)
    9.1
        CgA: Week 52: >2 ULN (n=11)
    63.6
        NSE: Baseline: <1 ULN (n=40)
    65.0
        NSE: Baseline: 1-2 ULN (n=40)
    25.0
        NSE: Baseline: >2 ULN (n=40)
    10.0
        NSE: Week 4: <1 ULN (n=35)
    62.9
        NSE: Week 4: 1-2 ULN (n=35)
    25.7
        NSE: Week 4: >2 ULN (n=35)
    11.4
        NSE: Week 12: <1 ULN (n=28)
    78.6
        NSE: Week 12: 1-2 ULN (n=28)
    17.9
        NSE: Week 12: >2 ULN (n=28)
    3.6
        NSE: Week 24: <1 ULN (n=20)
    80.0
        NSE: Week 24: 1-2 ULN (n=20)
    10.0
        NSE: Week 24: >2 ULN (n=20)
    10.0
        NSE: Week 36: <1 ULN (n=16)
    87.5
        NSE: Week 36: 1-2 ULN (n=16)
    6.3
        NSE: Week 36: >2 ULN (n=16)
    6.3
        NSE: Week 52: <1 ULN (n=11)
    63.6
        NSE: Week 52: 1-2 ULN (n=11)
    18.2
        NSE: Week 52: >2 ULN (n=11)
    18.2
    No statistical analyses for this end point

    Secondary: Influence of Biomarkers Expression on Locally and Centrally Assessed PFS

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    End point title
    		 Influence of Biomarkers Expression on Locally and Centrally Assessed PFS
    End point description
    The following biomarkers were investigated: Immunohistochemistry assay human somatostatin receptors 2 (SSTR2) including human epidermal growth factor receptor 2 (HER-2) score [0, 1+, 2+, 3+ and positive (+ve) versus negative (-ve)]; hormone receptor score (H-score) (from 0 to 300 as quantitative variable and +ve versus -ve); immunoreactive score (IRS) score (from 0 to 12 and reference for hazard ratio was 0-1). Ki67 index (from 0% to 100% and reference for hazard ratio was 4%-25%). O^6-methylguanine-DNA methyltransferase (MGMT) expression including percentage of +ve nuclei stained and methylated sites and H-score (from 0 to 300 as quantitative variable). For all these categories, higher score indicates a higher expression of biomarkers. Carcinoid type (typical or NET) was also investigated. Prognostic value of biomarkers expression at screening on PFS were assessed locally and centrally using univariate cox proportional hazard models. 9999= not calculated due to low number of events.
    End point type
    Secondary
    End point timeframe
    From Screening period (-4 weeks) up to Week 52
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40 [3]
    Units: hazard ratio
    number (confidence interval 95%)
        Local: SSTR2: HER-2 score; +ve (2+, 3+) (n=26)
    0.71 (0.26 to 1.92)
        Local: SSTR2: H-score; +ve (>= 50) (n=26)
    0.66 (0.25 to 1.71)
        Local: SSTR2: IRS score; 2-3 (n=26)
    0.31 (0.04 to 2.61)
        Local: SSTR2: IRS score; 4-8 (n=26)
    0.90 (0.31 to 2.61)
        Local: SSTR2: IRS score; 9-12 (n=26)
    0.12 (0.01 to 0.99)
        Local: Ki67: <4 (n=20)
    1.08 (0.13 to 8.93)
        Local: Ki67: >=25 (n=20)
    1.68 (0.37 to 7.70)
        Local: MGMT: +ve nuclei stained; +ve (>=5%) (n=26)
    2.06 (0.27 to 15.69)
        Local: MGMT: Methylated sites; +ve (>10%) (n=24)
    0.41 (0.05 to 3.20)
        Local: MGMT: H-score (n=26)
    1.00 (1.00 to 1.01)
        Local: Carcinoid type: Typical (n=40)
    1.05 (0.36 to 3.07)
        Local: Carcinoid type: Carcinoid NET (n=40)
    1.59 (0.64 to 3.93)
        Central: SSTR2: HER-2 score; +ve (2+, 3+) (n=26)
    0.50 (0.18 to 1.39)
        Central: SSTR2: H-score; +ve (>= 50) (n=26)
    0.36 (0.12 to 1.04)
        Central: SSTR2: IRS score; 2-3 (n=26)
    0.78 (0.16 to 3.92)
        Central: SSTR2: IRS score; 4-8 (n=26)
    0.88 (0.28 to 2.76)
        Central: SSTR2: IRS score; 9-12 (n=26)
    0.10 (0.01 to 0.89)
        Central: Ki67: <4 (n=20)
    0.00 (0.00 to 9999)
        Central: Ki67: >=25 (n=20)
    2.75 (0.55 to 13.76)
        Central:MGMT: +ve nuclei stained; +ve(>=5%) (n=26)
    2.11 (0.27 to 16.34)
        Central: MGMT: Methylated sites; +ve (>10%) (n=24)
    0.73 (0.16 to 3.33)
        Central: MGMT: H-score (n=26)
    1.00 (0.99 to 1.01)
        Central: Carcinoid type: Typical (n=40)
    0.99 (0.35 to 2.82)
        Central: Carcinoid type: Carcinoid NET (n=40)
    0.61 (0.20 to 1.89)
    Notes
    [3] - The ITT/Safety population. n = number of participants analysed in a specific model.
    No statistical analyses for this end point

    Secondary: Influence of Biomarkers Expression on Locally and Centrally Assessed ORR at Months 9 and 12

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    End point title
    		 Influence of Biomarkers Expression on Locally and Centrally Assessed ORR at Months 9 and 12
    End point description
    The following biomarkers were investigated: Immunohistochemistry assay SSTR2 including HER-2 score (0, 1+, 2+, 3+); H-score (from 0 to 300 as quantitative variable); IRS score (from 0 to 12). Ki67 index (from 0% to 100%). MGMT expression including percentage of +ve nuclei stained and methylated sites and H-score (from 0 to 300 as quantitative variable). For all these categories, higher score indicates a higher expression of biomarkers. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide). Less than 5 OR (CR or PR) events were reported, therefore this analysis was not performed.
    End point type
    Secondary
    End point timeframe
    Screening period, Months 9 and 12
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    0 [4]
    Units: odds ratio
        number (confidence interval 95%)
    ( to )
    Notes
    [4] - Less than 5 OR (CR or PR) events were reported, therefore this analysis was not performed.
    No statistical analyses for this end point

    Secondary: Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12

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    End point title
    		 Influence of Biomarkers Expression on Locally and Centrally Assessed DCR at Months 9 and 12
    End point description
    The following biomarkers were investigated: Immunohistochemistry assay SSTR2 including HER-2 score (0, 1+, 2+, 3+ and +ve versus -ve); H-score (from 0 to 300 as quantitative variable and +ve versus -ve); IRS score (from 0 to 12 and reference for odds ratio was 0-1). Ki67 index (from 0% to 100% and reference for odds ratio was 4%-25%). MGMT expression including percentage of +ve nuclei stained and methylated sites and H-score (from 0 to 300 as quantitative variable). For all these categories, higher score indicates a higher expression of biomarkers. Carcinoid type (typical or NET) was also investigated. Prognostic value of biomarkers expression at screening on DCR were assessed locally and centrally using univariate logistic regression models. M9= Month 9; M12= Month 12; Loc= Local assessment; Cntl= central assessment; -9999 and 9999= not calculated due to low number of events; -99999 and 99999= confidence interval could not be computed as odds ratio is <0.001.
    End point type
    Secondary
    End point timeframe
    Screening period, Months 9 and 12
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40 [5]
    Units: odds ratio
    number (confidence interval 95%)
        M9: Loc: SSTR2: HER-2 score; +ve (2+, 3+) (n=26)
    0.90 (0.18 to 4.55)
        M9: Loc: SSTR2: H-score; +ve (>= 50) (n=26)
    0.78 (0.16 to 3.79)
        M9: Loc: SSTR2: IRS score; 2-3 (n=26)
    9999 (-9999 to 9999)
        M9: Loc: SSTR2: IRS score; 4-8 (n=26)
    0.67 (0.07 to 6.11)
        M9: Loc: SSTR2: IRS score; 9-12 (n=26)
    12.00 (0.80 to 180.97)
        M9: Loc: Ki67: <4 (n=20)
    99999 (-99999 to 99999)
        M9: Loc: Ki67: >=25 (n=20)
    1.67 (0.09 to 31.87)
        M9: Loc:MGMT: +ve nuclei stained; +ve(>=5%) (n=26)
    99999 (-99999 to 99999)
        M9: Loc: MGMT: Methylated sites; +ve (>10%) (n=24)
    3.25 (0.25 to 41.91)
        M9: Loc: MGMT: H-score (n=26)
    0.99 (0.98 to 1.00)
        M9: Loc: Carcinoid type: Typical (n=40)
    0.16 (0.02 to 1.51)
        M9: Loc: Carcinoid type: Carcinoid NET (n=40)
    0.41 (0.09 to 2.00)
        M9: Cntl: SSTR2: HER-2 score; +ve (2+, 3+) (n=26)
    1.40 (0.26 to 7.58)
        M9: Cntl: SSTR2: H-score; +ve (>= 50) (n=26)
    2.25 (0.42 to 12.09)
        M9: Cntl: SSTR2: IRS score; 2-3 (n=26)
    3.00 (0.12 to 73.64)
        M9: Cntl: SSTR2: IRS score; 4-8 (n=26)
    0.67 (0.07 to 6.11)
        M9: Cntl: SSTR2: IRS score; 9-12 (n=26)
    12.00 (0.80 to 180.97)
        M9: Cntl: Ki67: <4 (n=20)
    99999 (-99999 to 99999)
        M9: Cntl: Ki67: >=25 (n=20)
    99999 (-99999 to 99999)
        M9: Cntl:MGMT: +ve nuclei stained;+ve(>=5%) (n=26)
    0.50 (0.03 to 9.08)
        M9: Cntl:MGMT: Methylated sites; +ve (>10%) (n=24)
    5.00 (0.38 to 66.01)
        M9: Cntl: MGMT: H-score (n=26)
    1.00 (0.99 to 1.01)
        M9: Cntl: Carcinoid type: Typical (n=40)
    99999 (-99999 to 99999)
        M9: Cntl: Carcinoid type: Carcinoid NET (n=40)
    1.06 (0.23 to 4.92)
        M12: Loc: SSTR2: HER-2 score; +ve (2+, 3+) (n=26)
    3.00 (0.28 to 31.63)
        M12: Loc: SSTR2: H-score; +ve (>= 50) (n=26)
    4.40 (0.42 to 46.24)
        M12: Loc: SSTR2: IRS score; 2-3 (n=26)
    99999 (-99999 to 99999)
        M12: Loc: SSTR2: IRS score; 4-8 (n=26)
    0.70 (0.04 to 13.18)
        M12: Loc: SSTR2: IRS score; 9-12 (n=26)
    10.50 (0.67 to 165.11)
        M12: Loc: Ki67: <4 (n=20)
    9999 (-9999 to 9999)
        M12: Loc: Ki67: >=25 (n=20)
    9999 (-9999 to 9999)
        M12: Loc:MGMT:+ve nuclei stained; +ve(>=5%) (n=26)
    0.20 (0.01 to 3.91)
        M12: Loc: MGMT: Methylated sites; +ve(>10%) (n=24)
    2.13 (0.15 to 29.66)
        M12: Loc: MGMT: H-score (n=26)
    0.99 (0.96 to 1.01)
        M12: Loc: Carcinoid type: Typical (n=40)
    0.46 (0.04 to 4.67)
        M12: Loc: Carcinoid type: Carcinoid NET (n=40)
    0.32 (0.03 to 3.15)
        M12: Cntl: SSTR2: HER-2 score; +ve (2+, 3+) (n=26)
    2.08 (0.19 to 23.30)
        M12: Cntl: SSTR2: H-score; +ve (>= 50) (n=26)
    3.00 (0.27 to 33.49)
        M12: Cntl: SSTR2: IRS score; 2-3 (n=26)
    99999 (-99999 to 99999)
        M12: Cntl: SSTR2: IRS score; 4-8 (n=26)
    99999 (-99999 to 99999)
        M12: Cntl: SSTR2: IRS score; 9-12 (n=26)
    10.50 (0.67 to 165.11)
        M12: Cntl: Ki67: <4 (n=20)
    99999 (-99999 to 99999)
        M12: Cntl: Ki67: >=25 (n=20)
    99999 (-99999 to 99999)
        M12: Cntl:MGMT:+ve nuclei stained;+ve(>=5%) (n=26)
    0.14 (0.01 to 2.94)
        M12: Cntl:MGMT: Methylated sites; +ve(>10%) (n=24)
    3.00 (0.20 to 44.36)
        M12: Cntl: MGMT: H-score (n=26)
    0.99 (0.96 to 1.01)
        M12: Cntl: Carcinoid type: Typical (n=40)
    0.57 (0.05 to 6.08)
        M12: Cntl: Carcinoid type: Carcinoid NET (n=40)
    0.40 (0.04 to 4.11)
    Notes
    [5] - The ITT/Safety population. n = number of participants analysed in a specific model.
    No statistical analyses for this end point

    Secondary: Coefficient of Agreement Between Central and Local Assessment of Tumour Radiological Response at Month 9

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    End point title
    		 Coefficient of Agreement Between Central and Local Assessment of Tumour Radiological Response at Month 9
    End point description
    Differences between central radiology review and local investigator review were assessed according to the DCR status and the number of agreements and disagreements between the evaluators (central versus local) along with the p-values from the kappa test. A kappa statistic was used to evaluate the concordance between the central and the local review. The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide).
    End point type
    Secondary
    End point timeframe
    Month 9
    End point values
    		 Lanreotide ATG plus Temozolomide
    Number of subjects analysed
    40
    Units: kappa coefficient
        number (confidence interval 95%)
    0.71 (0.48 to 0.94)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events were collected from the start of the first treatment (Day 1) until 4 weeks after the end of the last study treatment, up to a maximum of 52 weeks.
    Adverse event reporting additional description
    The ITT/Safety population included all participants who received at least 1 dose of study medication (either lanreotide ATG 120 mg or temozolomide). Number of deaths (all causes) occurred in both treatment period and follow-up period were reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Lanreotide ATG plus Temozolomide
    Reporting group description
    		 Lanreotide ATG 120 mg was administered by deep subcutaneous injection on Day 1 (baseline) and every 28 days for up to 52 weeks. Participants also received temozolomide 250 mg capsule orally once daily for 5 consecutive days every 28 days for up to 52 weeks. The dose of temozolomide could subsequently be reduced to 180 mg daily for 5 consecutive days every 28 days in case of bone marrow toxicity.

    Serious adverse events
    		 Lanreotide ATG plus Temozolomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 40 (22.50%)
         number of deaths (all causes)
    9
         number of deaths resulting from adverse events
    2
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Lanreotide ATG plus Temozolomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 40 (95.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Hypertension
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    3
    Hypotension
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 40 (20.00%)
         occurrences all number
    8
    Pyrexia
         subjects affected / exposed
    6 / 40 (15.00%)
         occurrences all number
    6
    Pain
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Influenza like illness
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    3
    Fatigue
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    4
    Chest pain
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    6
    Dyspnoea
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    3
    Dyspnoea exertional
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Haemoptysis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Pleural thickening
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Pneumonitis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    7 / 40 (17.50%)
         occurrences all number
    7
    Blood cholesterol increased
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    5
    Platelet count decreased
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    7
    Blood creatinine increased
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Blood triglycerides increased
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    5
    White blood cell count decreased
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Glucose tolerance decreased
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Transaminases increased
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Vitamin b12 decreased
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Tachyarrhythmia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    5
    Sciatica
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Dysgeusia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Lymphopenia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    21 / 40 (52.50%)
         occurrences all number
    42
    Vomiting
         subjects affected / exposed
    13 / 40 (32.50%)
         occurrences all number
    24
    Diarrhoea
         subjects affected / exposed
    12 / 40 (30.00%)
         occurrences all number
    36
    Constipation
         subjects affected / exposed
    8 / 40 (20.00%)
         occurrences all number
    26
    Abdominal pain
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Dry mouth
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Haematochezia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    3
    Bile duct obstruction
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Hepatic steatosis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    5
    Pruritus
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Erythema
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    5
    Musculoskeletal pain
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Arthralgia
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    3
    Pain in extremity
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    4
    Pain in jaw
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Angular cheilitis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Bacteriuria
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Ear infection
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Fungal infection
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Oral herpes
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    6
    Hypocalcaemia
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Vitamin d deficiency
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Decreased appetite
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Hypercalcaemia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2016
    A detailed description of optional sub study procedures (MGMT methylation and blood samples) was added. As consequence, the number and volume of blood samples to be collected was reduced. The analysis of MGMT methylation on tissue samples was added. This had no further impact on the participants and was to provide stronger data to the study. Participants with asymptomatic cholilithiasis, previously excluded from the study, could be enrolled. This was to guarantee as many participants as possible access to the study treatment.
    16 Nov 2017
    Amended to specify the timelines for adverse events collection, end of study visit and to specify a maximum delay for investigational medicinal product administration. Addition of specifications related to direct bilirubin assessment and specification that the description of the sub-study analysis will be performed through a separate statistical analysis plan and that the results will be reported separately.

    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
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