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    Clinical Trial Results:
    A multicentre, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in patients with inoperable, progressive, somatostatin receptor positive midgut carcinoid tumours

    Summary
    EudraCT number
    2011-005049-11
    Trial protocol
    GB   ES   IT   BE   PT   FR   AT  
    Global end of trial date
    18 Jan 2021

    Results information
    Results version number
    v3(current)
    This version publication date
    28 Apr 2022
    First version publication date
    22 Oct 2021
    Other versions
    v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    AAA-III-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01578239
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    CAAA601A12301: Novartis
    Sponsors
    Sponsor organisation name
    Advanced Accelerator Applications SA
    Sponsor organisation address
    20, rue Diesel, Saint-Genis Pouilly, Switzerland, 01630
    Public contact
    Novartis Clinical Disclosure Office, Advanced Accelerator Applications SA, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Novartis Clinical Disclosure Office, Advanced Accelerator Applications SA, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare progression-free survival (PFS) after treatment with 177Lu-DOTA0-Tyr3-octreotate (Lutathera) plus best supportive care (30 mg Octreotide LAR) to treatment with high-dose (60 mg) Octreotide LAR in participants with inoperable, progressive [as determined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1], somatostatin receptor positive, well-differentiated neuroendocrine tumors of the small bowel (midgut carcinoid tumors)
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Sep 2012
    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
    Belgium: 6
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    United States: 137
    Country: Number of subjects enrolled
    Spain: 11
    Worldwide total number of subjects
    231
    EEA total number of subjects
    70
    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)
    119
    From 65 to 84 years
    110
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study was conducted in 41 sites across 8 countries.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    177Lu-DOTA0-Tyr3-Octreotate
    Arm description
    * 30 mg Octreotide LAR treatment for symptom control continued until the end of study, unless the participant progressed or died. * Treatment consisted of a cumulative administered radioactivity of 29.6 Giga Becquerel (GBq) (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate: Four administrations of 7.4 GBq (200 mCi). * Concomitant amino acids were given with each administration for kidney protection. * 177Lu-DOTA0-Tyr3-Octreotate was administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections were allowed.
    Arm type
    Experimental

    Investigational medicinal product name
    Octreotide LAR
    Investigational medicinal product code
    Other name
    SANDOSTATIN LAR, Octreotide
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg Octreotide LAR treatment was given to the participants until the end of study for symptom control purpose, unless the participant progressed or died.

    Investigational medicinal product name
    177Lu-DOTA0-Tyr3-Octreotate
    Investigational medicinal product code
    Other name
    Lutathera
    Pharmaceutical forms
    Kit for radiopharmaceutical preparation
    Routes of administration
    Intravenous use
    Dosage and administration details
    Four administrations of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity.

    Arm title
    Octreotide LAR
    Arm description
    * 60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections were allowed.
    Arm type
    Active comparator

    Investigational medicinal product name
    Octreotide LAR
    Investigational medicinal product code
    Other name
    SANDOSTATIN LAR, Octreotide
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg Octreotide LAR treatment was given to the participants every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died.

    Number of subjects in period 1
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
    Started
    117
    114
    Full Analysis set (FAS)
    117
    114
    Safety Analysis Set (SAF)
    111
    112
    FAS-Entered long-term follow-up
    101
    99
    Completed
    50
    13
    Not completed
    67
    101
         Physician decision
    17
    17
         Non-compliance
    2
    -
         Not specified
    6
    1
         Adverse event, non-fatal
    13
    10
         Progressive Disease
    19
    64
         Consent withdrawn by subject
    10
    9
    Period 2
    Period 2 title
    Long-term Follow-Up Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    177Lu-DOTA0-Tyr3-Octreotate
    Arm description
    * 30 mg Octreotide LAR treatment for symptom control continued until the end of study, unless the participant progressed or died. * Treatment consisted of a cumulative administered radioactivity of 29.6 Giga Becquerel (GBq) (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate: Four administrations of 7.4 GBq (200 mCi). * Concomitant amino acids were given with each administration for kidney protection. * 177Lu-DOTA0-Tyr3-Octreotate was administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections were allowed.
    Arm type
    Experimental

    Investigational medicinal product name
    177Lu-DOTA0-Tyr3-Octreotate
    Investigational medicinal product code
    Other name
    Lutathera
    Pharmaceutical forms
    Kit for radiopharmaceutical preparation
    Routes of administration
    Intravenous use
    Dosage and administration details
    Four administrations of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity.

    Investigational medicinal product name
    Octreotide LAR
    Investigational medicinal product code
    Other name
    SANDOSTATIN LAR, Octreotide
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg Octreotide LAR treatment was given to the participants until the end of study for symptom control purpose, unless the participant progressed or died.

    Arm title
    Octreotide LAR
    Arm description
    * 60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections were allowed.
    Arm type
    Active comparator

    Investigational medicinal product name
    Octreotide LAR
    Investigational medicinal product code
    Other name
    SANDOSTATIN LAR, Octreotide
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg Octreotide LAR treatment was given to the participants every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died.

    Number of subjects in period 2
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
    Started
    101
    99
    Completed
    24
    19
    Not completed
    77
    80
         Not specified
    2
    2
         Adverse event, serious fatal
    69
    64
         Consent withdrawal
    4
    10
         Lost to follow-up
    2
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    177Lu-DOTA0-Tyr3-Octreotate
    Reporting group description
    * 30 mg Octreotide LAR treatment for symptom control continued until the end of study, unless the participant progressed or died. * Treatment consisted of a cumulative administered radioactivity of 29.6 Giga Becquerel (GBq) (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate: Four administrations of 7.4 GBq (200 mCi). * Concomitant amino acids were given with each administration for kidney protection. * 177Lu-DOTA0-Tyr3-Octreotate was administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections were allowed.

    Reporting group title
    Octreotide LAR
    Reporting group description
    * 60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections were allowed.

    Reporting group values
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR Total
    Number of subjects
    117 114 231
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    62 57 119
        From 65-84 years
    55 55 110
        85 years and over
    0 2 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    63.4 ± 9.34 64.0 ± 9.80 -
    Sex: Female, Male
    Units:
        Female
    54 60 114
        Male
    63 54 117
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    1 0 1
        Black or African American
    5 5 10
        Hispanic
    6 3 9
        White
    93 96 189
        Other
    0 1 1
        Not Applicable
    12 9 21

    End points

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    End points reporting groups
    Reporting group title
    177Lu-DOTA0-Tyr3-Octreotate
    Reporting group description
    * 30 mg Octreotide LAR treatment for symptom control continued until the end of study, unless the participant progressed or died. * Treatment consisted of a cumulative administered radioactivity of 29.6 Giga Becquerel (GBq) (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate: Four administrations of 7.4 GBq (200 mCi). * Concomitant amino acids were given with each administration for kidney protection. * 177Lu-DOTA0-Tyr3-Octreotate was administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections were allowed.

    Reporting group title
    Octreotide LAR
    Reporting group description
    * 60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections were allowed.
    Reporting group title
    177Lu-DOTA0-Tyr3-Octreotate
    Reporting group description
    * 30 mg Octreotide LAR treatment for symptom control continued until the end of study, unless the participant progressed or died. * Treatment consisted of a cumulative administered radioactivity of 29.6 Giga Becquerel (GBq) (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate: Four administrations of 7.4 GBq (200 mCi). * Concomitant amino acids were given with each administration for kidney protection. * 177Lu-DOTA0-Tyr3-Octreotate was administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections were allowed.

    Reporting group title
    Octreotide LAR
    Reporting group description
    * 60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections were allowed.

    Primary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    Progression Free Survival (PFS) was defined as the time from randomization to documented centrally assessed disease progression, as evaluated by the Independent Review Committee (IRC), or death due to any cause. If a participant had no centrally assessed progression and had not died at the time of the primary endpoint analysis, the participant was regarded as censored in the context of a time to event analysis at the date of last evaluable tumor assessment. Disease progression was determined by objective tumor response status using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1).
    End point type
    Primary
    End point timeframe
    From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months
    End point values
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
    Number of subjects analysed
    117
    114
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    8.5 (5.8 to 9.1)
    Statistical analysis title
    Progression Free Survival (PFS)
    Comparison groups
    177Lu-DOTA0-Tyr3-Octreotate v Octreotide LAR
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.177
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.108
         upper limit
    0.289
    Notes
    [1] - Derived from a two-sided test between the two groups

    Secondary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR)
    End point description
    Objective Response Rate (ORR) was calculated as the proportion of patients with tumour size reduction (sum of partial responses (PR) and complete responses (CR)) according to RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months
    End point values
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
    Number of subjects analysed
    102
    100
    Units: Percentage of Participants
        number (confidence interval 95%)
    14.7 (7.8 to 21.6)
    4.0 (0.2 to 7.8)
    Statistical analysis title
    Objective Response Rate (ORR)
    Comparison groups
    177Lu-DOTA0-Tyr3-Octreotate v Octreotide LAR
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0141
    Method
    Fisher exact
    Confidence interval

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall Survival (OS) was defined as the time from the date of randomization to the date of death due to any cause or the date of last contact (censored observation) prior to the date of the data cut-off, and during the entire study period (i.e. the treatment period plus follow-up).
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of death from any cause up to final safety cut-off date reached on 18Jan2021, assessed up to approximately 100 months
    End point values
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
    Number of subjects analysed
    117
    114
    Units: Months
        median (confidence interval 95%)
    48.0 (37.4 to 55.2)
    36.3 (25.9 to 51.7)
    Statistical analysis title
    Overall Survival (OS)
    Comparison groups
    177Lu-DOTA0-Tyr3-Octreotate v Octreotide LAR
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.3039
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.17

    Secondary: Rate of Overall Survival (OS)

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    End point title
    Rate of Overall Survival (OS)
    End point description
    Survival estimates were collected every 12 Months up to 60 Months to compare OS between the two treatment groups.
    End point type
    Secondary
    End point timeframe
    12 months, 24 months, 36 months, 48 months, 60 months
    End point values
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
    Number of subjects analysed
    117
    114
    Units: Percentage of Survival Estimates
    number (confidence interval 95%)
        12 months
    91.0 (84.0 to 95.1)
    79.7 (70.8 to 86.1)
        24 months
    76.0 (66.7 to 83.0)
    62.7 (52.6 to 71.2)
        36 months
    61.4 (51.4 to 69.9)
    50.1 (40.0 to 59.4)
        48 months
    49.5 (39.5 to 58.6)
    41.8 (31.8 to 51.4)
        60 months
    37.1 (27.8 to 46.4)
    35.4 (25.7 to 45.2)
    Statistical analysis title
    Rate of Overall Survival (OS)
    Comparison groups
    177Lu-DOTA0-Tyr3-Octreotate v Octreotide LAR
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.3039
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.17

    Secondary: Time to Tumour Progression (TTP)

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    End point title
    Time to Tumour Progression (TTP)
    End point description
    Time to Tumour Progression (TTP) was defined as the time from randomization to progression centrally assessed. It included patients who dropped out due to toxicity, but omitted patients who died without measured progression (censored to last follow-up date or death date).
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months
    End point values
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
    Number of subjects analysed
    117
    114
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    8.7 (6.0 to 11.1)
    Statistical analysis title
    Time to Tumour Progression (TTP)
    Comparison groups
    177Lu-DOTA0-Tyr3-Octreotate v Octreotide LAR
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.137
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.077
         upper limit
    0.242

    Secondary: Duration of Response (DoR)

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    End point title
    Duration of Response (DoR)
    End point description
    The Duration of Response (DoR) was defined as the time from initially meeting the criteria for response (CR or PR) until the time of progression by RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months
    End point values
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
    Number of subjects analysed
    15
    4
    Units: Months
        median (confidence interval 95%)
    999 (2.8 to 999)
    1.9 (1.9 to 999)
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events

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    End point title
    Number of Participants with Adverse Events
    End point description
    The distribution of adverse events was done via the analysis of frequencies for Adverse Event (AEs), Serious Adverse Event (SAEs) and Deaths, through the monitoring of relevant clinical and laboratory safety parameters.
    End point type
    Secondary
    End point timeframe
    From informed consent signature through study completion reached at final safety cutoff date on 18July2021, assessed up to approximately 101 Months
    End point values
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
    Number of subjects analysed
    111
    112
    Units: Participants
        Adverse Events (AEs)
    105
    90
        Serious Adverse Events (SAEs)
    40
    31
        Deaths during treatment period
    4
    5
        Deaths during follow-up period
    66
    63
    No statistical analyses for this end point

    Secondary: Change from Baseline in the EORTC QLQ-C30 Questionnaire

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    End point title
    Change from Baseline in the EORTC QLQ-C30 Questionnaire
    End point description
    The Quality of Life Questionnaire C30 (QLQ-C30) was developed by the European Organization for Research and Treatment of Cancer (EORTC) to assess quality of life in cancer patients. It includes five function domains (physical, emotional, social, role, cognitive), eight symptoms (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. Subjects respond on a four-point scale from "not at all" to "very much" for most items. Raw scores are linearly transformed so each score ranged a 0-100, where higher scores indicate worse symptoms (e.g., more severe/worsened) and lower scores indicate less symptoms (e.g., less severe/improvement).
    End point type
    Secondary
    End point timeframe
    Inclusion (Baseline) (BL), Week 72, Week 120
    End point values
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
    Number of subjects analysed
    111
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Physical functioning: chg from BL@wk 72 (n=33,11)
    3.232 ± 12.4857
    -4.242 ± 10.0101
        Physical functioning: chg from BL@wk 120 (n=2,0)
    -3.333 ± 4.7140
    -4.242 ± 10.0101
        Role functioning: chg from BL@wk 72 (n=33,11)
    5.051 ± 33.1989
    -3.030 ± 16.3608
        Role functioning: chg from BL@wk 120 (n=2,0)
    8.333 ± 11.7851
    76.305 ± 30.3682
        Emotional functioning: chg from BL@wk 72 (n=33,11)
    7.744 ± 22.6602
    6.061 ± 17.9083
        Emotional functioning: chg from BL@wk 120 (n=2,0)
    12.500 ± 5.8926
    999 ± 999
        Cognitive functioning: chg from BL@wk 72 (n=33,11)
    5.556 ± 15.9571
    1.515 ± 13.8535
        Cognitive functioning: chg from BL@wk 120 (n=2,0)
    16.667 ± 23.5702
    6.061 ± 17.9083
        Social functioning: chg from BL@wk 72 (n=33,11)
    8.586 ± 28.9039
    -7.576 ± 18.8025
        Social functioning: chg from BL@wk 120 (n=2,0)
    8.333 ± 35.3553
    81.746 ± 22.6461
        Global Health Status: chg from BL@wk 72 (n=33,11)
    5.556 ± 21.4155
    1.515 ± 10.4205
        Global Health Status: chg from BL@wk 120 (n=2,0)
    -16.667 ± 0.0000
    999 ± 999
        Fatigue: chg from BL@wk 72 (n=33,11)
    -7.239 ± 24.7084
    -2.020 ± 13.8939
        Fatigue: chg from BL@wk 120 (n=2,0)
    11.111 ± 0.0000
    -7.576 ± 18.8025
        Nausea & Vomiting: chg from BL@wk 72 (n=33,11)
    -4.545 ± 15.1799
    -4.545 ± 7.7850
        Nausea & Vomiting: chg from BL@wk 120 (n=2,0)
    0.000 ± 0.0000
    66.369 ± 23.0841
        Pain: chg from BL@wk 72 (n=33,11)
    -8.586 ± 22.4850
    -3.030 ± 10.0504
        Pain: chg from BL@wk 120 (n=2,0)
    0.000 ± 23.5702
    999 ± 999
        Dyspnoea: chg from BL@wk 72 (n=33,11)
    -3.030 ± 22.6134
    3.030 ± 27.7070
        Dyspnoea: chg from BL@wk 120 (n=2,0)
    0.000 ± 0.0000
    -2.020 ± 13.8939
        Insomnia: chg from BL@wk 72 (n=33,11)
    0.000 ± 26.3523
    6.061 ± 29.1288
        Insomnia: chg from BL@wk 120 (n=2,0)
    33.333 ± 47.1405
    9.839 ± 19.3099
        Appetite loss: chg from BL@wk 72 (n=33,11)
    -8.081 ± 20.4639
    9.091 ± 21.5557
        Appetite loss: chg from BL@wk 120 (n=2,0)
    0.000 ± 0.0000
    999 ± 999
        Constipation: chg from BL@wk 72 (n=33,11)
    0.000 ± 18.6339
    0.000 ± 14.9071
        Constipation: chg from BL@wk 120 (n=2,0)
    0.000 ± 0.0000
    -3.030 ± 10.0504
        Diarrhoea: chg from BL@wk 72 (n=33,11)
    -12.121 ± 36.1499
    -3.030 ± 27.7070
        Diarrhoea: chg from BL@wk 120 (n=2,0)
    -16.667 ± 23.5702
    18.072 ± 26.6977
        Financial diffic.: chg from BL@wk 72 (n=33,11)
    -7.071 ± 33.0798
    6.061 ± 20.1008
        Financial diffic.: chg from BL@wk 120 (n=2,0)
    -16.667 ± 70.7107
    999 ± 999
    No statistical analyses for this end point

    Secondary: Change from Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21)

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    End point title
    Change from Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21)
    End point description
    The Quality of Life GI Neuroendocrine Tumor survey (QLQ GINET21) contains a total of 21 items: four single-item assessments relating to muscle and/or bone pain (MBP), body image (BI), information (INF) and sexual functioning (SX), together with 17 items organized into five proposed scales: endocrine symptoms (ED; three items), GI symptoms (GI; five items), treatment-related symptoms (TR; three items), social functioning (SF) and disease-related worries (DRW; three items). The response format of the questionnaire is a four-point Likert scale. Responses are linearly transformed to a 0-100 scale using EORTC guidelines, with higher scores reflecting more severe symptoms.
    End point type
    Secondary
    End point timeframe
    Inclusion (Baseline) (BL), Week 72, Week 120
    End point values
    177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
    Number of subjects analysed
    112
    111
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Endocrine scale: chg from BL@wk 72 (n=33,11)
    -8.754 ± 20.1762
    -11.111 ± 21.0819
        Endocrine scale: chg from BL@wk 120 (n=2,0)
    0.000 ± 0.0000
    -11.111 ± 21.0819
        G.I. scale: chg from BL@wk 72 (n=33,11)
    -2.727 ± 15.3083
    2.424 ± 10.0101
        G.I. scale: chg from BL@wk 120 (n=2,0)
    -13.333 ± 0.0000
    22.718 ± 19.9443
        Treatment scale: chg from BL@wk 72 (n=21,5)
    -8.995 ± 14.9563
    0.000 ± 11.1111
        Treatment scale: chg from BL@wk 120 (n=1,0)
    -16.667 ± 999
    999 ± 999
        Social function scale: chg from BL@wk 72 (n=33,11)
    -7.576 ± 23.3985
    -7.576 ± 21.1217
        Social function scale: chg from BL@wk 120 (n=2,0)
    11.111 ± 0.0000
    0.000 ± 11.1111
        Diseases rel. wo.: chg from BL@wk 72 (n=33,11)
    -6.061 ± 27.9289
    1.010 ± 33.7765
        Diseases rel. wo.: chg from BL@wk 120 (n=2,0)
    33.333 ± 31.4270
    36.145 ± 26.2073
        Muscle/Bone pain: chg from BL@wk 72 (n=33,10)
    -5.051 ± 33.4594
    -16.667 ± 36.0041
        Muscle/Bone pain: chg from BL@wk 120 (n=2,0)
    -16.667 ± 23.5702
    999 ± 999
        Sexual function: chg from BL@wk 72 (n=21,7)
    6.349 ± 40.3031
    14.286 ± 17.8174
        Sexual function: chg from BL@wk 120 (n=2,0)
    50.000 ± 70.7107
    1.010 ± 33.7765
        Information/Com.: chg from BL@wk 72 (n=33,11)
    -4.040 ± 26.0309
    -12.121 ± 30.8139
        Information/Com.: chg from BL@wk 120 (n=2,0)
    0.000 ± 0.0000
    34.146 ± 32.7000
        Body image: chg from BL@wk 72 (n=33,11)
    -4.040 ± 18.1766
    -3.030 ± 17.9787
        Body image: chg from BL@wk 120 (n=2,0)
    16.667 ± 23.5702
    999 ± 999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent signature through study completion reached at final safety cutoff date on 18July2021, assessed up to approximately 101 Months.
    Adverse event reporting additional description
    Any sign or symptom that occurs after written informed consent provided.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Lu-DOTA-Tyr-Octreotate
    Reporting group description
    Lu-DOTA-Tyr-Octreotate

    Reporting group title
    Total
    Reporting group description
    Total

    Reporting group title
    Octreotide LAR
    Reporting group description
    Octreotide LAR

    Serious adverse events
    Lu-DOTA-Tyr-Octreotate Total Octreotide LAR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 111 (36.04%)
    71 / 223 (31.84%)
    31 / 112 (27.68%)
         number of deaths (all causes)
    70
    138
    68
         number of deaths resulting from adverse events
    1
    1
    0
    Vascular disorders
    Inferior vena cava syndrome
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Coronary artery bypass
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 223 (0.90%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carcinoid crisis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer stage I
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 111 (1.80%)
    7 / 223 (3.14%)
    5 / 112 (4.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 7
    0 / 5
    Neoplasm progression
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Prostate cancer
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    2 / 111 (1.80%)
    2 / 223 (0.90%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    Refractory cytopenia with multilineage dysplasia
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour invasion
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Complication of device insertion
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 111 (1.80%)
    4 / 223 (1.79%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    Generalised oedema
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Injection site hypersensitivity
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    2 / 111 (1.80%)
    2 / 223 (0.90%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriospasm coronary
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Silent myocardial infarction
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cough
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    2 / 111 (1.80%)
    2 / 223 (0.90%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Refractory cytopenia with unilineage dysplasia
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombotic cerebral infarction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 111 (2.70%)
    4 / 223 (1.79%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 223 (0.90%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 223 (0.90%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant bowel obstruction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 223 (1.35%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 111 (1.80%)
    4 / 223 (1.79%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 111 (3.60%)
    5 / 223 (2.24%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Acute prerenal failure
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 223 (0.90%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Lu-DOTA-Tyr-Octreotate Total Octreotide LAR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 111 (94.59%)
    195 / 223 (87.44%)
    90 / 112 (80.36%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    16 / 111 (14.41%)
    26 / 223 (11.66%)
    10 / 112 (8.93%)
         occurrences all number
    19
    31
    12
    Hypertension
         subjects affected / exposed
    13 / 111 (11.71%)
    21 / 223 (9.42%)
    8 / 112 (7.14%)
         occurrences all number
    20
    28
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 111 (8.11%)
    17 / 223 (7.62%)
    8 / 112 (7.14%)
         occurrences all number
    12
    20
    8
    Fatigue
         subjects affected / exposed
    43 / 111 (38.74%)
    73 / 223 (32.74%)
    30 / 112 (26.79%)
         occurrences all number
    62
    93
    31
    Influenza like illness
         subjects affected / exposed
    6 / 111 (5.41%)
    10 / 223 (4.48%)
    4 / 112 (3.57%)
         occurrences all number
    13
    17
    4
    Oedema peripheral
         subjects affected / exposed
    18 / 111 (16.22%)
    28 / 223 (12.56%)
    10 / 112 (8.93%)
         occurrences all number
    24
    34
    10
    Pyrexia
         subjects affected / exposed
    8 / 111 (7.21%)
    11 / 223 (4.93%)
    3 / 112 (2.68%)
         occurrences all number
    10
    13
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 111 (2.70%)
    11 / 223 (4.93%)
    8 / 112 (7.14%)
         occurrences all number
    3
    16
    13
    Anxiety
         subjects affected / exposed
    13 / 111 (11.71%)
    19 / 223 (8.52%)
    6 / 112 (5.36%)
         occurrences all number
    14
    21
    7
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 111 (6.31%)
    14 / 223 (6.28%)
    7 / 112 (6.25%)
         occurrences all number
    10
    20
    10
    Blood bilirubin increased
         subjects affected / exposed
    7 / 111 (6.31%)
    10 / 223 (4.48%)
    3 / 112 (2.68%)
         occurrences all number
    9
    13
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 111 (4.50%)
    13 / 223 (5.83%)
    8 / 112 (7.14%)
         occurrences all number
    7
    19
    12
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 111 (6.31%)
    15 / 223 (6.73%)
    8 / 112 (7.14%)
         occurrences all number
    8
    18
    10
    Blood creatinine increased
         subjects affected / exposed
    7 / 111 (6.31%)
    13 / 223 (5.83%)
    6 / 112 (5.36%)
         occurrences all number
    10
    16
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 111 (6.31%)
    16 / 223 (7.17%)
    9 / 112 (8.04%)
         occurrences all number
    10
    20
    10
    Platelet count decreased
         subjects affected / exposed
    13 / 111 (11.71%)
    15 / 223 (6.73%)
    2 / 112 (1.79%)
         occurrences all number
    18
    20
    2
    Lymphocyte count decreased
         subjects affected / exposed
    12 / 111 (10.81%)
    14 / 223 (6.28%)
    2 / 112 (1.79%)
         occurrences all number
    22
    24
    2
    Weight decreased
         subjects affected / exposed
    9 / 111 (8.11%)
    17 / 223 (7.62%)
    8 / 112 (7.14%)
         occurrences all number
    11
    21
    10
    White blood cell count decreased
         subjects affected / exposed
    7 / 111 (6.31%)
    8 / 223 (3.59%)
    1 / 112 (0.89%)
         occurrences all number
    12
    14
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    6 / 111 (5.41%)
    12 / 223 (5.38%)
    6 / 112 (5.36%)
         occurrences all number
    7
    13
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 111 (16.22%)
    26 / 223 (11.66%)
    8 / 112 (7.14%)
         occurrences all number
    22
    32
    10
    Lymphopenia
         subjects affected / exposed
    18 / 111 (16.22%)
    18 / 223 (8.07%)
    0 / 112 (0.00%)
         occurrences all number
    24
    24
    0
    Thrombocytopenia
         subjects affected / exposed
    16 / 111 (14.41%)
    16 / 223 (7.17%)
    0 / 112 (0.00%)
         occurrences all number
    29
    29
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    12 / 111 (10.81%)
    21 / 223 (9.42%)
    9 / 112 (8.04%)
         occurrences all number
    15
    25
    10
    Cough
         subjects affected / exposed
    12 / 111 (10.81%)
    20 / 223 (8.97%)
    8 / 112 (7.14%)
         occurrences all number
    14
    22
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    19 / 111 (17.12%)
    29 / 223 (13.00%)
    10 / 112 (8.93%)
         occurrences all number
    23
    36
    13
    Syncope
         subjects affected / exposed
    6 / 111 (5.41%)
    8 / 223 (3.59%)
    2 / 112 (1.79%)
         occurrences all number
    6
    8
    2
    Headache
         subjects affected / exposed
    21 / 111 (18.92%)
    27 / 223 (12.11%)
    6 / 112 (5.36%)
         occurrences all number
    28
    55
    27
    Dysgeusia
         subjects affected / exposed
    9 / 111 (8.11%)
    11 / 223 (4.93%)
    2 / 112 (1.79%)
         occurrences all number
    9
    12
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    18 / 111 (16.22%)
    32 / 223 (14.35%)
    14 / 112 (12.50%)
         occurrences all number
    23
    39
    16
    Constipation
         subjects affected / exposed
    11 / 111 (9.91%)
    17 / 223 (7.62%)
    6 / 112 (5.36%)
         occurrences all number
    12
    18
    6
    Abdominal pain upper
         subjects affected / exposed
    6 / 111 (5.41%)
    8 / 223 (3.59%)
    2 / 112 (1.79%)
         occurrences all number
    9
    13
    4
    Abdominal pain
         subjects affected / exposed
    28 / 111 (25.23%)
    49 / 223 (21.97%)
    21 / 112 (18.75%)
         occurrences all number
    41
    64
    23
    Diarrhoea
         subjects affected / exposed
    32 / 111 (28.83%)
    52 / 223 (23.32%)
    20 / 112 (17.86%)
         occurrences all number
    44
    69
    25
    Dyspepsia
         subjects affected / exposed
    7 / 111 (6.31%)
    14 / 223 (6.28%)
    7 / 112 (6.25%)
         occurrences all number
    11
    23
    12
    Vomiting
         subjects affected / exposed
    59 / 111 (53.15%)
    68 / 223 (30.49%)
    9 / 112 (8.04%)
         occurrences all number
    126
    138
    12
    Nausea
         subjects affected / exposed
    74 / 111 (66.67%)
    87 / 223 (39.01%)
    13 / 112 (11.61%)
         occurrences all number
    162
    176
    14
    Flatulence
         subjects affected / exposed
    7 / 111 (6.31%)
    13 / 223 (5.83%)
    6 / 112 (5.36%)
         occurrences all number
    7
    13
    6
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    7 / 111 (6.31%)
    10 / 223 (4.48%)
    3 / 112 (2.68%)
         occurrences all number
    9
    13
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    13 / 111 (11.71%)
    15 / 223 (6.73%)
    2 / 112 (1.79%)
         occurrences all number
    14
    16
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 111 (10.81%)
    23 / 223 (10.31%)
    11 / 112 (9.82%)
         occurrences all number
    16
    32
    16
    Musculoskeletal pain
         subjects affected / exposed
    5 / 111 (4.50%)
    11 / 223 (4.93%)
    6 / 112 (5.36%)
         occurrences all number
    5
    13
    8
    Muscle spasms
         subjects affected / exposed
    7 / 111 (6.31%)
    9 / 223 (4.04%)
    2 / 112 (1.79%)
         occurrences all number
    11
    14
    3
    Back pain
         subjects affected / exposed
    15 / 111 (13.51%)
    26 / 223 (11.66%)
    11 / 112 (9.82%)
         occurrences all number
    21
    33
    12
    Pain in extremity
         subjects affected / exposed
    12 / 111 (10.81%)
    18 / 223 (8.07%)
    6 / 112 (5.36%)
         occurrences all number
    16
    23
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    24 / 111 (21.62%)
    36 / 223 (16.14%)
    12 / 112 (10.71%)
         occurrences all number
    37
    49
    12
    Hyperglycaemia
         subjects affected / exposed
    11 / 111 (9.91%)
    21 / 223 (9.42%)
    10 / 112 (8.93%)
         occurrences all number
    17
    30
    13
    Hypokalaemia
         subjects affected / exposed
    9 / 111 (8.11%)
    19 / 223 (8.52%)
    10 / 112 (8.93%)
         occurrences all number
    10
    21
    11
    Hyponatraemia
         subjects affected / exposed
    7 / 111 (6.31%)
    11 / 223 (4.93%)
    4 / 112 (3.57%)
         occurrences all number
    8
    14
    6
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    7 / 111 (6.31%)
    14 / 223 (6.28%)
    7 / 112 (6.25%)
         occurrences all number
    7
    15
    8

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Aug 2012
    The protocol was amended to include the following main changes: ● The definitions of PFS, TTP, and OS were modified so that they were based on the time from the date of randomization, instead of the time from the date of first treatment ● The exclusion criteria were supplemented with the criterion ‘lactation’ ● Clarification about safety assessments and the performance of additional safety assessments regarding blood chemistry and urine tests was added to the study schedule for both treatment groups ● Instructions were added to ensure that laboratory parameters met required treatment criteria before administration of study drug, and participant observation after treatment with the study drug was extended ● Further details on the DSMB role and activities were added ● Further details on the substudy conduct and data analysis were implemented ● Appendices 15 (Recommended Precautions for Participants Treated with 177Lu-DOTA0-Tyr3-octreotate (Lutathera)) and 17 (Randomization Procedure of Participants after Enrolment) were modified and Appendix 19 (Determination of Lutathera Administered Radioactivity) were added to the protocol.
    24 Jul 2013
    The protocol was amended to include the following main changes: ● Per FDA request, the biased coin randomization scheme was replaced by a stratified permuted block randomization scheme with a balanced ratio (1:1) between the 2 treatment groups and the stratification for specific center enrolment was deleted (at the time of the randomization scheme change, 28 participants were already randomized) ● The method to control the family-wise type I error rate for OS and ORR was included as well as a detailed description of the statistical analysis for OS ● The end of study definition was modified and the description of the primary analysis adapted accordingly ● Participant replacement for the primary analysis was excluded and the primary log-rank test further specified ● Clarifications were added regarding the conduct of the urinalysis, the CT/MRI timings, the allowed tumor location, the study population characteristics, timing and procedures of the OctreoScan®, and the allowed time-windows for the Octreotide LAR injections ● Discontinuation criteria for individual participants were specified in more detail ● Further options for additional allowed amino acid solutions, details on the drug administration procedures in the Octreotide LAR group, details about the administration procedures of rescue medication, and details about the handling of study medication were added ● Further details on SAE and AESI reporting were included.
    23 Sep 2013
    The protocol was amended to include the following main changes to the conduct and procedures of the NETTER-1 substudy: ● Additional details on the dosimetry substudy procedures were added with regard to the performance of further optional dosimetry ● The number of sites participating in the substudy was increased.
    25 Mar 2014
    The protocol amended to include these main changes: ● Sample size adjusted, follow-up period increased from 3 to 5 years to detect statistically significant and clinically relevant difference in OS between the 2 study groups ● Study design adapted so that primary analysis conducted after 74 PFS events (74 centrally confirmed disease progression or death events) ● Secondary endpoints of DoR and PFS2 added as exploratory objectives ●End of Study (EOS) defined as reaching 158 deaths or 5 years had elapsed since the date of randomization of the last randomized participant, whichever occurred first ● Specifications added for the use of unstratified log-rank test in the primary analysis of PFS ● Details added on Dose Modifying Toxicity criteria and procedures ● Timing for safety assessments adapted to comply with new EOS ● Flowcharts and visits of the treatment/assessment period were adapted to comply with the new study design ● Substudy exclusion criteria regarding subsequent treatments modified ● Definitions regarding screening failures, study termination, and study withdrawal were added to the discontinuation criteria for individual participants ● A description about the handling of discrepancies in the evaluation of the progressive status between Investigator and central assessor added ● Clarification on procedures for dropouts, replacements and deliberate treatment interruption added ● Details on Octreotide LAR administration added ● Details on supportive information from histology added, clarifications on the CT/MRI scan timing and procedures, specifications on concomitant medication collection ● Recommendations added regarding amino acids solution infusion for treatment of nausea/vomiting and the use of anti-emetics ● Substudy updated with additional information on ECG assessments, collection of physical examination, vital signs, timing of the exams in relation to the 177Lu-DOTA0-Tyr3-octreotate treatment, dosimetry, PK, and cardiac assessments
    05 Jun 2014
    The protocol was amended to include the following main changes to the conduct and procedures of the substudy: ● Recruitment, randomization, and data analysis details for the substudy were specified.

    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.
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