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    Clinical Trial Results:
    Phase III, randomised, double-blind, stratified comparative, placebo controlled, parallel group, multicentre study to assess the effect of deep subcutaneous injections of lanreotide Autogel 120 mg administered every 28 days on tumour progression free survival in patients with non functioning entero-pancreatic endocrine tumour.

    Summary
    EudraCT number
    		 2005-004904-35
    Trial protocol
    		 GB   NL   BE   DK   CZ   GR   SE   DE   AT   IT   SK   ES  
    Global end of trial date
    09 Apr 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jun 2016
    First version publication date
    04 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Protocol2-55-52030-726
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IPSEN PHARMA SAS
    Sponsor organisation address
    65 quai Georges Gorse, Boulogne Billancourt Cedex , France, 92650
    Public contact
    Medical Director, Gastroenterology, Ipsen Pharma S.A.S, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Gastroenterology, Ipsen Pharma S.A.S, 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
    11 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Apr 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to assess the effect of lanreotide Autogel 120 mg administered every 28 days compared to placebo, on progression-free survival in patients with well or moderately differentiated non functioning entero-pancreatic endocrine tumour.
    Protection of trial subjects
    This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and with the ethical principles laid down in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jun 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 6 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 41
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 30
    Country: Number of subjects enrolled
    India: 4
    Worldwide total number of subjects
    204
    EEA total number of subjects
    170
    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)
    111
    From 65 to 84 years
    91
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 264 subjects were screened at 48 investigational sites in 14 countries (Austria, Belgium, Czech Republic, Denmark, France, Germany, India, Italy, Poland, Slovakia, Spain, Sweden, United Kingdom and the United States of America). 204 subjects were randomised to receive study treatment in the Intent to treat (ITT) population.

    Pre-assignment
    Screening details
    		 A total of 264 subjects were screened for this study. There were 101 subjects randomised to receive lanreotide Autogel 120 mg and 103 subjects randomised to receive placebo. These 204 randomised subjects form the ITT population for analysis.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Two sets of individual sealed code break envelopes were prepared by an Ipsen Randomisation Manager to enable code break procedures of individual subjects without compromising the blind of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lanreotide (Autogel Formulation)
    Arm description
    		 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide Autogel 120 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    120 mg

    Arm title
    		 Placebo
    Arm description
    		 Placebo: Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NA

    Number of subjects in period 1
    		Lanreotide (Autogel Formulation) Placebo
    Started
    101
    103
    Completed
    56
    34
    Not completed
    45
    69
         Consent withdrawn by subject
    3
    5
         Physician decision
    6
    9
         Disease progression
    27
    49
         Not otherwise specified
    4
    1
         Adverse event
    3
    3
         Protocol deviation
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lanreotide (Autogel Formulation)
    Reporting group description
    		 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo: Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks.

    Reporting group values
    		 Lanreotide (Autogel Formulation) Placebo Total
    Number of subjects
    		 101 103 204
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63 ( 10 ) 62 ( 11 ) -
    Gender categorical
    Units: Subjects
        Female
    		 48 49 97
        Male
    		 53 54 107
    Race (NIH/OMB)
    Units: Subjects
        Asian
    		 2 5 7
        Black or African American
    		 2 2 4
        White
    		 97 96 193
    Neuroendocrine tumour (NET) origin
    Units: Subjects
        Pancreas
    		 42 49 91
        Midgut
    		 33 40 73
        Hindgut
    		 11 3 14
        Unknown/Other
    		 15 11 26
    Chromogranin A
    Chromogranin A is an NET marker. ULN: upper limit of normal
    Units: Subjects
        ≤1 × ULN
    		 33 34 67
        1–2 × ULN
    		 25 18 43
        >2 × ULN
    		 41 48 89
        Unknown
    		 2 3 5
    Time since diagnosis
    Units: months
        arithmetic mean (standard deviation)
    		 32.6 ( 46.1 ) 34.4 ( 41.4 ) -
    5-HIAA
    n= 44 and 37
    Units: µmol/d
        arithmetic mean (standard deviation)
    		 163.2 ( 194 ) 285.8 ( 406.4 ) -
    Gastrin
    n = 33 and 35
    Units: ng/L
        arithmetic mean (standard deviation)
    		 258.4 ( 220 ) 450.3 ( 353.2 ) -
    Pancreatic polypeptide
    n = 29 and 34
    Units: pmol/L
        arithmetic mean (standard deviation)
    		 164.03 ( 35.53 ) 167.43 ( 38.81 ) -

    End points

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    End points reporting groups
    Reporting group title
    Lanreotide (Autogel Formulation)
    Reporting group description
    		 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo: Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks.

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS) [1] [2]
    End point description
    Time from randomization to first documentation of disease progression, or death. Disease progression centrally assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 Analysis based on the intent-to-treat (ITT) population which comprised 204 randomised subjects. For the Lanreotide (Autogel Formulation) arm: Median (95% CI) was Not reached during the 96 week fixed duration study.
    End point type
    Primary
    End point timeframe
    From randomisation up to the last tumour assessment (scheduled at 96 weeks). Radiological scans were performed every 12 weeks during the first year and every 24 weeks during the second year
    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: Due to system limitations, data is presented for single arm. Hence statistical analysis details could not be included. Statistical analyses details: P-value: < 0.001, Method: Logrank, Hazard ratio (HR): 0.47, 95% Confidence interval level: (0.3, 0.73) The log rank test was stratified according to progression status at baseline and prior therapy. No p-value adjustment for multiple comparisons.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For the Lanreotide (Autogel Formulation) arm: Median (95% CI) was Not reached during the 96 week fixed duration study. Due to system limitations, data cannot be represented for this arm, hence this arm is not included.
    End point values
    		 Placebo
    Number of subjects analysed
    103
    Units: Weeks
        median (confidence interval 95%)
    72 (48.6 to 96)
    No statistical analyses for this end point

    Secondary: Percentage of Patients Alive & Without Disease Progression

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    End point title
    		 Percentage of Patients Alive & Without Disease Progression
    End point description
    Percentage of patients still ongoing (or completing at Week 96) without centrally assessed disease progression or death at Weeks 48 and 96. Analysis based on the intent-to-treat (ITT) population which comprised 204 randomised subjects.
    End point type
    Secondary
    End point timeframe
    Week 48 & 96
    End point values
    		 Lanreotide (Autogel Formulation) Placebo
    Number of subjects analysed
    101
    103
    Units: Percentage of participants
        Week 48
    66
    49
        Week 96
    53
    25
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Profile of Lanreotide

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    End point title
    		 Pharmacokinetic Profile of Lanreotide [3]
    End point description
    Pharmacokinetic Profile of Lanreotide assessed by mean serum concentration at specified timepoints Analysis based on the intent-to-treat (ITT) population which comprised 101 randomised subjects who received lanreotide
    End point type
    Secondary
    End point timeframe
    Week 4, 12, 24, 36, 48, 72, 96
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only to analyze the pharmacokinetic profile of the study drug and hence placebo arm is not included
    End point values
    		 Lanreotide (Autogel Formulation)
    Number of subjects analysed
    101
    Units: ng/mL
    arithmetic mean (standard deviation)
        At Week 4 predose (n=81)
    2.5 ( 0.46 )
        At Week 12 predose (n=87)
    5 ( 0.42 )
        At Week 24 predose (n=74)
    6.1 ( 0.44 )
        At Week 36 predose (n=67)
    6.2 ( 0.39 )
        At Week 48 predose (n=62)
    6.6 ( 0.45 )
        At Week 72 predose (n=52)
    6.8 ( 0.44 )
        At Week 96 predose (n=48)
    6.6 ( 0.39 )
    No statistical analyses for this end point

    Secondary: Change in the Global Health Status Quality of Life Assessment

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    End point title
    		 Change in the Global Health Status Quality of Life Assessment
    End point description
    Analysis based on the intent-to-treat (ITT) population which comprised 193 randomised subjects with valid assessment. Transformed scores from European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire responses (QLQ)-C30. Questionnaire response scores range from 0 to 100. Higher scores indicate best possible Quality of Life.
    End point type
    Secondary
    End point timeframe
    Week 12 to Week 96 (last visit)
    End point values
    		 Lanreotide (Autogel Formulation) Placebo
    Number of subjects analysed
    95
    98
    Units: score on a scale
        least squares mean (standard error)
    -5.2 ( 3.7 )
    -4.9 ( 3.7 )
    No statistical analyses for this end point

    Secondary: Percentage of Patients With a Greater Than or Equal to 50% Decrease in Plasma Chromogranin A (CgA) Levels

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    End point title
    		 Percentage of Patients With a Greater Than or Equal to 50% Decrease in Plasma Chromogranin A (CgA) Levels
    End point description
    Analysis based on the subgroup of subjects with an elevated plasma CgA values. Subjects with a gastrinoma were excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    Week 12 to Week 96 (last visit)
    End point values
    		 Lanreotide (Autogel Formulation) Placebo
    Number of subjects analysed
    64
    64
    Units: percentage of participants
        number (not applicable)
    42.2
    4.7
    No statistical analyses for this end point

    Secondary: Percentage of Patients Still Alive Based on Available Overall Survival Data

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    End point title
    		 Percentage of Patients Still Alive Based on Available Overall Survival Data
    End point description
    Overall survival defined as the time from randomisation to death due to any cause. Subjects were followed for overall survival beyond study completion/withdrawal via annual telephone contact until the last subject completed the study. Analysis based on the intent-to-treat (ITT) population which comprised 204 randomised subjects.
    End point type
    Secondary
    End point timeframe
    Randomisation to death or last visit, up to 321 weeks
    End point values
    		 Lanreotide (Autogel Formulation) Placebo
    Number of subjects analysed
    101
    103
    Units: percentage of participants
    84
    77
    No statistical analyses for this end point

    Secondary: Time to Disease Progression

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    End point title
    		 Time to Disease Progression [4]
    End point description
    The KM (Kaplan-Meier) estimates for the time to centrally assessed disease progression are presented. Analysis based on the intent-to-treat (ITT) population which comprised 204 randomised subjects. For the Lanreotide (Autogel Formulation) arm: Median (95% CI) was Not reached fixed duration study.
    End point type
    Secondary
    End point timeframe
    up to 103 Weeks
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For the Lanreotide (Autogel Formulation) arm: Median (95% CI) was Not reached during the 96 week fixed duration study. Due to system limitations, data cannot be represented for this arm, hence this arm is not included.
    End point values
    		 Placebo
    Number of subjects analysed
    103
    Units: Weeks
        median (confidence interval 95%)
    72.1 (48.6 to 96.1)
    No statistical analyses for this end point

    Secondary: Mean Change from baseline in Tumour Marker Levels for 5-Hydroxyindoleacetic acid (5-HIAA)

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    End point title
    		 Mean Change from baseline in Tumour Marker Levels for 5-Hydroxyindoleacetic acid (5-HIAA)
    End point description
    ITT Subjects with Elevated Values at Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (visit 2) and 96 weeks (last post-baseline value)
    End point values
    		 Lanreotide (Autogel Formulation) Placebo
    Number of subjects analysed
    43
    36
    Units: µmol/d
        arithmetic mean (standard deviation)
    -74 ( 136.2 )
    148.1 ( 237.1 )
    No statistical analyses for this end point

    Secondary: Mean Change from baseline in Tumour Marker Levels for Gastrin

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    End point title
    		 Mean Change from baseline in Tumour Marker Levels for Gastrin
    End point description
    ITT Subjects with Elevated Values at Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (visit 2) and 96 weeks (last post-baseline value)
    End point values
    		 Lanreotide (Autogel Formulation) Placebo
    Number of subjects analysed
    33
    35
    Units: ng/L
        arithmetic mean (standard deviation)
    -91.1 ( 152.2 )
    -21.1 ( 287.3 )
    No statistical analyses for this end point

    Secondary: Mean Change from baseline in Tumour Marker Levels for Pancreatic polypeptide

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    End point title
    		 Mean Change from baseline in Tumour Marker Levels for Pancreatic polypeptide
    End point description
    ITT Subjects with Elevated Values at Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (visit 2) and 96 weeks (last post-baseline value)
    End point values
    		 Lanreotide (Autogel Formulation) Placebo
    Number of subjects analysed
    26
    32
    Units: pmol/L
        arithmetic mean (standard deviation)
    -107.59 ( 49.49 )
    -10.2 ( 59.6 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 96 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Lanreotide (Autogel Formulation)
    Reporting group description
    		 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo: Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks.

    Serious adverse events
    		 Lanreotide (Autogel Formulation) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 101 (24.75%)
    32 / 103 (31.07%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    2
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bronchial carcinoma
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hypertensive crisis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 101 (0.00%)
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic ulcer
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve stenosis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 101 (2.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    4 / 101 (3.96%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 101 (1.98%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 101 (0.99%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 101 (0.99%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Diarrhoea
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Biliary fistula
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic necrosis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Toxic nodular goitre
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 101 (2.97%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lanreotide (Autogel Formulation) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    88 / 101 (87.13%)
    92 / 103 (89.32%)
    Investigations
    Weight decreased
         subjects affected / exposed
    9 / 101 (8.91%)
    9 / 103 (8.74%)
         occurrences all number
    9
    10
    Pancreatic enzymes decreased
         subjects affected / exposed
    6 / 101 (5.94%)
    0 / 103 (0.00%)
         occurrences all number
    7
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 101 (12.87%)
    5 / 103 (4.85%)
         occurrences all number
    16
    5
    Flushing
         subjects affected / exposed
    4 / 101 (3.96%)
    6 / 103 (5.83%)
         occurrences all number
    4
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 101 (15.84%)
    11 / 103 (10.68%)
         occurrences all number
    19
    19
    Dizziness
         subjects affected / exposed
    9 / 101 (8.91%)
    1 / 103 (0.97%)
         occurrences all number
    12
    1
    Lethargy
         subjects affected / exposed
    5 / 101 (4.95%)
    4 / 103 (3.88%)
         occurrences all number
    13
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    11 / 101 (10.89%)
    16 / 103 (15.53%)
         occurrences all number
    15
    18
    Asthenia
         subjects affected / exposed
    8 / 101 (7.92%)
    6 / 103 (5.83%)
         occurrences all number
    8
    6
    Injection site pain
         subjects affected / exposed
    8 / 101 (7.92%)
    4 / 103 (3.88%)
         occurrences all number
    30
    10
    Oedema peripheral
         subjects affected / exposed
    5 / 101 (4.95%)
    7 / 103 (6.80%)
         occurrences all number
    5
    12
    Pyrexia
         subjects affected / exposed
    4 / 101 (3.96%)
    6 / 103 (5.83%)
         occurrences all number
    6
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    35 / 101 (34.65%)
    37 / 103 (35.92%)
         occurrences all number
    57
    75
    Abdominal pain
         subjects affected / exposed
    23 / 101 (22.77%)
    18 / 103 (17.48%)
         occurrences all number
    32
    34
    Vomiting
         subjects affected / exposed
    17 / 101 (16.83%)
    10 / 103 (9.71%)
         occurrences all number
    21
    28
    Nausea
         subjects affected / exposed
    15 / 101 (14.85%)
    13 / 103 (12.62%)
         occurrences all number
    28
    22
    Flatulence
         subjects affected / exposed
    12 / 101 (11.88%)
    9 / 103 (8.74%)
         occurrences all number
    13
    12
    Constipation
         subjects affected / exposed
    11 / 101 (10.89%)
    14 / 103 (13.59%)
         occurrences all number
    13
    16
    Abdominal pain upper
         subjects affected / exposed
    7 / 101 (6.93%)
    9 / 103 (8.74%)
         occurrences all number
    7
    15
    Abdominal discomfort
         subjects affected / exposed
    5 / 101 (4.95%)
    3 / 103 (2.91%)
         occurrences all number
    8
    4
    Dyspepsia
         subjects affected / exposed
    3 / 101 (2.97%)
    8 / 103 (7.77%)
         occurrences all number
    3
    11
    Haemorrhoids
         subjects affected / exposed
    0 / 101 (0.00%)
    7 / 103 (6.80%)
         occurrences all number
    0
    7
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    15 / 101 (14.85%)
    7 / 103 (6.80%)
         occurrences all number
    16
    7
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    6 / 101 (5.94%)
    1 / 103 (0.97%)
         occurrences all number
    7
    2
    Cough
         subjects affected / exposed
    5 / 101 (4.95%)
    3 / 103 (2.91%)
         occurrences all number
    5
    8
    Oropharyngeal pain
         subjects affected / exposed
    5 / 101 (4.95%)
    3 / 103 (2.91%)
         occurrences all number
    5
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    7 / 101 (6.93%)
    3 / 103 (2.91%)
         occurrences all number
    8
    3
    Alopecia
         subjects affected / exposed
    5 / 101 (4.95%)
    4 / 103 (3.88%)
         occurrences all number
    5
    4
    Pruritus
         subjects affected / exposed
    5 / 101 (4.95%)
    5 / 103 (4.85%)
         occurrences all number
    5
    17
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    11 / 101 (10.89%)
    11 / 103 (10.68%)
         occurrences all number
    12
    11
    Arthralgia
         subjects affected / exposed
    10 / 101 (9.90%)
    10 / 103 (9.71%)
         occurrences all number
    15
    11
    Musculoskeletal pain
         subjects affected / exposed
    7 / 101 (6.93%)
    3 / 103 (2.91%)
         occurrences all number
    8
    6
    Muscle spasms
         subjects affected / exposed
    5 / 101 (4.95%)
    4 / 103 (3.88%)
         occurrences all number
    5
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 101 (8.91%)
    17 / 103 (16.50%)
         occurrences all number
    10
    23
    Urinary tract infection
         subjects affected / exposed
    8 / 101 (7.92%)
    11 / 103 (10.68%)
         occurrences all number
    13
    13
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 101 (2.97%)
    6 / 103 (5.83%)
         occurrences all number
    5
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 101 (9.90%)
    9 / 103 (8.74%)
         occurrences all number
    11
    11
    Diabetes mellitus
         subjects affected / exposed
    9 / 101 (8.91%)
    4 / 103 (3.88%)
         occurrences all number
    9
    5
    Dehydration
         subjects affected / exposed
    5 / 101 (4.95%)
    1 / 103 (0.97%)
         occurrences all number
    7
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jan 2007
    Protocol Amendment 1 • Inclusion criteria modification addition of subject with gastrinomas and tumours of unknown origin; extension of the window for the tumour biopsy. • Clarification on safety assessment (removal of local tolerance and disease progression from adverse event, role of the DSMC). • Clarification on procedures (blood sampling conditions and study drug injection). • Clarification on statistical definitions and testing. • Removal of plans for an interim analysis on the study and addition of a SSR.
    30 Jul 2007
    Protocol Amendment 2 • Modification of the inclusion criteria (tumour biopsy and CT-scan window • Specification about the randomisation list to be provided to the independent statistician in charge of reporting for DSMC.
    30 Apr 2008
    Protocol Amendment 3 • Introduction of the plan for an extension study to enable subjects to continue to receive lanreotide Autogel after completion of 96 weeks of treatment and to allow any subject that progressed while on placebo, to enter into the extension study. A request would be made by the Investigator for a potential code break due to centrally assessed disease progression confirmed by RECIST to verify subject’s entry into the extension study.
    04 Apr 2009
    Protocol Amendment 4 • Change of saline solution in the United States of America. • Change of Sponsor name and address and of coordinating office name.
    05 Mar 2010
    Protocol Amendment 5 • Addition of hepatic tumour load evaluation on subject CT/MRI scan at baseline visit. • Removal of restriction regarding centres recruiting more than 20 subjects. • Addition of sensitivity analyses to investigate the robustness of the results of the primary efficacy analysis.
    11 Feb 2011
    Protocol Amendment 6 • Changes in response to US FDA to use the log rank test instead of the Cox PH model originally planned for the primary analysis of PFS, to follow up subjects for OS and to analyse OS as a secondary endpoint. • Planned update to CRF and ICF to collect OS data. • Change to the number of SSRs to one in response to advice from the FDA that this should be sufficient.
    28 Feb 2012
    Protocol Amendment 7 •To replace Ipsen Pharma S.A. with new laboratories, performing the PK evaluation and anti lanreotide antibody testing, due to site closure.

    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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