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    Clinical Trial Results:
    Phase III, multicentre, open study to assess the efficacy and safety profiles of the co-administration of lanreotide Autogel 120 mg (administered via deep subcutaneous injections every 28 days) and pegvisomant 40 to 120 mg per week (administered via subcutaneous route once or twice a week) in acromegalic patients failing to respond to lanreotide Autogel 120 mg alone

    Summary
    EudraCT number
    		 2006-000297-72
    Trial protocol
    		 SE   GR   DE   CZ   DK   IT   GB  
    Global end of trial date
    27 Oct 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 May 2016
    First version publication date
    03 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2-55-52030-727
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00383708
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ipsen Pharma
    Sponsor organisation address
    65, Quai Georges Gorse, Boulogne-Billancourt, France, 92100
    Public contact
    Medical Director, Endocrinology., Ipsen Pharma, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Endocrinology., Ipsen Pharma, 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
    22 Jan 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Oct 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of the co-administration of lanreotide Autogel 120 mg (administered via deep sub-cutaneous injections every 28 days) and pegvisomant (administered at 40 to 120 mg per week via sub-cutaneous injection given once or twice a week) on IGF-1 levels over 28 weeks in acromegalic patients. The primary endpoint was the percentage of acromegalic patients with normalised (age and sex adjusted) IGF-1 level at the end of the co-treatment period.
    Protection of trial subjects
    This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonization (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
    02 Oct 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Greece: 18
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Spain: 12
    Worldwide total number of subjects
    125
    EEA total number of subjects
    125
    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)
    103
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All subjects enrolled over 25 study centers located in 10 European countries.

    Pre-assignment
    Screening details
    		 A total of 125 subjects screened.

    Pre-assignment period milestones
    Number of subjects started
    		 125
    Number of subjects completed
    		 92

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not meet entry criteria: 32
    Reason: Number of subjects
    		 Consent withdrawn: 1
    Period 1
    Period 1 title
    Run-in period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All Subjects
    Arm description
    		 Lanreotide Autogel 120 mg which was administered every 28 days via deep Subcutaneous route in the upper external quadrant of the buttock.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide Autogel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lanreotide Autogel 120 mg which was administered every 28 days via deep Subcutaneous route in the upper external quadrant of the buttock.

    Number of subjects in period 1
    		All Subjects
    Started
    92
    Completed
    85
    Not completed
    7
         Protocol violation
    4
         Other
    1
         Adverse event
    2
    Period 2
    Period 2 title
    Treated Co-administration
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Titration Basis
    Arm description
    		 Lanreotide Autogel 120 mg was co-administered with Pegvisomant at various doses as Co-administration dose 1 in visit 4 and 5, Co-administration dose 2 in visit 6 and 7, Co-administration dose 3 in visit 7 and 8 and Co-administration dose 4 in visit 9 and 10.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide Autogel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lanreotide Autogel 120 mg which was administered every 28 days via deep Subcutaneous route in the upper external quadrant of the buttock.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is the initial phase of study 'Run-in period' and period 2 is the second phase 'Co-administration phase' which is of the main interest of this study and hence Period 2 is considered as the baseline period.
    Number of subjects in period 2 [2] [3]
    		Titration Basis
    Started
    57
    Completed
    52
    Not completed
    5
         Adverse event
    5
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide data is reported for all subjects who got enrolled in the study. However, baseline data is reported only for the subjects who entered Period 2: 'Co-administration phase'
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 85 patients completed period 1 (run-in), however, of these for 28 patients IGF-1 values assessed at Visit 4 made them ineligible for period 2 (co-administration) and were withdrawn at Visit 4.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Titration Basis
    Reporting group description
    		 Lanreotide Autogel 120 mg was co-administered with Pegvisomant at various doses as Co-administration dose 1 in visit 4 and 5, Co-administration dose 2 in visit 6 and 7, Co-administration dose 3 in visit 7 and 8 and Co-administration dose 4 in visit 9 and 10.

    Reporting group values
    		 Titration Basis Total
    Number of subjects
    		 57 57
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.6 ± 12.7 -
    Gender categorical
    Units: Subjects
        Female
    		 28 28
        Male
    		 29 29
    Race
    Units: Subjects
        Asian
    		 2 2
        Caucasian
    		 55 55
    Diabetic Status at Study Entry
    Diabetic status at study entry was derived from medical history at Visit 1.
    Units: Subjects
        Diabetic
    		 15 15
        Non diabetic
    		 42 42
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 172.4 ± 10.5 -
    IGF-1 at Baseline
    Baseline is defined as Visit 3.
    Units: z-score
        arithmetic mean (standard deviation)
    		 6.485 ± 4.113 -

    End points

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    End points reporting groups
    Reporting group title
    All Subjects
    Reporting group description
    		 Lanreotide Autogel 120 mg which was administered every 28 days via deep Subcutaneous route in the upper external quadrant of the buttock.
    Reporting group title
    Titration Basis
    Reporting group description
    		 Lanreotide Autogel 120 mg was co-administered with Pegvisomant at various doses as Co-administration dose 1 in visit 4 and 5, Co-administration dose 2 in visit 6 and 7, Co-administration dose 3 in visit 7 and 8 and Co-administration dose 4 in visit 9 and 10.

    Primary: The percentage of subjects with acromegaly with a normalised IGF-1 level

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    End point title
    		 The percentage of subjects with acromegaly with a normalised IGF-1 level [1]
    End point description
    The intention to treat (ITT) population is co-administered subjects having at least one baseline and at least one post baseline assessment of the primary efficacy endpoint. Method of estimation is Clopper-Pearson and p-value is < 0.0001.
    End point type
    Primary
    End point timeframe
    At visit 9 and 10
    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: End point data is reported for single arm, hence statistical details is mentioned in description.
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Percentage of subjects
    number (not applicable)
        Serum IGF-1 normalised at end of co-administration
    57.9
    No statistical analyses for this end point

    Primary: The percentage of subjects with Serum IGF-1 Normalisation by Previous Treatment and Final DosePegvisomant at End of Co-administration

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    End point title
    		 The percentage of subjects with Serum IGF-1 Normalisation by Previous Treatment and Final DosePegvisomant at End of Co-administration [2]
    End point description
    ITT population Previously treated with pegvisomant: Method of estimation is Clopper-Pearson and p-value is 0.1654. Previously treated with lanreotide Autogel: Method of estimation is Clopper-Pearson and p-value is 0.0115. Previously treated with octreotide LAR: Method of estimation is Clopper-Pearson and p-value is 0.0003.
    End point type
    Primary
    End point timeframe
    At visit 9 and 10
    Notes
    [2] - 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: End point data is reported for single arm, hence statistical details is mentioned in description.
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Percentage of subjects
    number (not applicable)
        Previous Treatment: Pegvisomant (N=13)
    46.2
        Previous Treatment: Lanreotide Autogel (N=24)
    54.2
        Previous Treatment: Octreotide LAR (N=20)
    70
        Final Dose Pegvisomant: 40 mg/week (N=13)
    76.9
        Final Dose Pegvisomant: 60 mg/week (N= 13)
    61.5
        Final Dose Pegvisomant: 80 mg/week (N=16)
    75
        Final Dose Pegvisomant: 40 mg 2x/week (N=5)
    60
        Final Dose Pegvisomant: 60 mg 2x/week (N=10)
    0
    No statistical analyses for this end point

    Primary: The percentage of subjects with Serum IGF-1 Normalisation at End of Co-administration by Diabetic Status

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    End point title
    		 The percentage of subjects with Serum IGF-1 Normalisation at End of Co-administration by Diabetic Status [3]
    End point description
    ITT population Diabetic subjects: Method of estimation is Clopper-Pearson and p-value is 0.084. Non-Diabetic subjects: Method of estimation is Clopper-Pearson and p-value is < 0.0001.
    End point type
    Primary
    End point timeframe
    At visit 9 and 10
    Notes
    [3] - 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: End point data is reported for single arm, hence statistical details is mentioned in description.
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Percentage of subjects
    number (not applicable)
        Diabetic Subjects (N=19)
    47.4
        Non Diabetic Subjects (N=38)
    63.2
    No statistical analyses for this end point

    Secondary: Percentage of subjects normalised at least once in serum IGF-1 levels

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    End point title
    		 Percentage of subjects normalised at least once in serum IGF-1 levels
    End point description
    The intention to treat (ITT) population is co-administered subjects having at least one baseline and at least one post baseline assessment of the primary efficacy endpoint. Estimation method is Clopper-Pearson and for both categories p-value is < 0.0001.
    End point type
    Secondary
    End point timeframe
    At visit 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Percentage of subjects
    number (not applicable)
        During co-administration, while taking final dose
    66.7
        During co-administration, at any time
    78.9
    No statistical analyses for this end point

    Secondary: Serum growth hormone level

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    End point title
    		 Serum growth hormone level
    End point description
    The intention to treat (ITT) population is co-administered subjects having at least one baseline and at least one post baseline assessment of the primary efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months)
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: ng/ml
    arithmetic mean (standard deviation)
        Visit 3 (n= 57)
    6.1 ± 7.2
        Change at visit 11 (n= 52)
    6.6 ± 9.9
    No statistical analyses for this end point

    Secondary: Growth Hormone Binding Protein

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    End point title
    		 Growth Hormone Binding Protein
    End point description
    The intention to treat (ITT) population is co-administered subjects having at least one baseline and at least one post baseline assessment of the primary efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months).
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: pmol/L
    arithmetic mean (standard deviation)
        Visit 3 (n= 57)
    274 ± 184
        Change at visit 11 (n= 52)
    841 ± 302
    No statistical analyses for this end point

    Secondary: Acid Labile Subunit (ALS)

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    End point title
    		 Acid Labile Subunit (ALS)
    End point description
    The intention to treat (ITT) population is co-administered subjects having at least one baseline and at least one post baseline assessment of the primary efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months).
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: mIU/ml
    arithmetic mean (standard deviation)
        Visit 3 (n= 57)
    1842 ± 497
        Change at visit 11 (n= 52)
    -561 ± 528
    No statistical analyses for this end point

    Secondary: Prolactin level

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    End point title
    		 Prolactin level
    End point description
    The intention to treat (ITT) population is co-administered subjects having at least one baseline and at least one post baseline assessment of the primary efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months).
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: μg/l
    arithmetic mean (standard deviation)
        Visit 3 (n= 57)
    25.8 ± 49.2
        Change at visit 11 (n= 52)
    -0.1 ± 8.9
    No statistical analyses for this end point

    Secondary: Percentage of subjects with serum growth hormone lesser or equal 2.5 ng/ml

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    End point title
    		 Percentage of subjects with serum growth hormone lesser or equal 2.5 ng/ml
    End point description
    The intention to treat (ITT) population is co-administered subjects having at least one baseline and at least one post baseline assessment of the primary efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months)
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Percentage of subjects
    number (not applicable)
        Visit 3 (n= 57)
    38.6
        At visit 11 (n=52)
    25
    No statistical analyses for this end point

    Secondary: Change in acromegaly symptoms during the study

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    End point title
    		 Change in acromegaly symptoms during the study
    End point description
    The intention to treat (ITT) population is co-administered subjects having at least one baseline and at least one post baseline assessment of the primary efficacy endpoint. Headache, excessive perspiration, fatigue, soft tissue swelling and arthralgia were to be assessed with scores ranging from 0 (no symptoms) to 8 (severe, incapacitating symptoms). Symptoms were assessed by the subject in paper format before any other procedure planned during the visit.
    End point type
    Secondary
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months)
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Units on scale
    arithmetic mean (standard deviation)
        Arthralgia, visit 3 (n=56)
    3.7 ± 2.3
        Arthralgia, change at visit 11 (n=50)
    -0.7 ± 1.5
        Excessive Perspiration, visit 3 (n=56)
    2.1 ± 2
        Excessive Perspiration, change at visit 11 (n=50)
    -0.4 ± 1.9
        Fatigue, visit 3 (n=56)
    3.2 ± 2.2
        Fatigue, change at visit 11 (n=50)
    -0.2 ± 1.6
        Headache, visit 3 (n=55)
    2.2 ± 2.3
        Headache, change at visit 11 (n=49)
    -0.4 ± 1.6
        Soft Tissue Swelling, visit 3 (n=56)
    2.1 ± 1.9
        Soft Tissue Swelling, change at visit 11 (n=50)
    -0.6 ± 1.9
    No statistical analyses for this end point

    Secondary: Change in acromegaly quality of life (ACROQOL) assessments during the study

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    End point title
    		 Change in acromegaly quality of life (ACROQOL) assessments during the study
    End point description
    ITT population; Relationship (Relnship); Dimension(Dim) ACROQOL is a new health-related quality of life questionnaire for patients with acromegaly: development & psychometric properties. Questionnaire will be filled by each patient in paper forms, before any other procedure planned during visit,at same time as acromegaly symptoms assessment. Questionnaire is simple & time required to complete is approximately 7 minutes. It is self- administered,so filling out ACROQoL requires quiet place,privacy & prior explanation by investigator. Investigator should emphasise that responses are confidential, explain all questions, & ensure patient understands them. Investigator will specify that only 1 response is allowed for each question, & there is no incorrect response (patient chooses option that best describes his/her situation). Investigator should remind that all questions should be carefully read before answering, patient should check there is no missing answer in completed questionnaire
    End point type
    Secondary
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months)
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Units on scale
    arithmetic mean (standard deviation)
        Global Score-V3 n=57
    55.2 ± 19.8
        Global Score-change at V11 n=52
    2.4 ± 9.1
        Physical Dimensions Score-V3 n=57
    50.5 ± 24.1
        Physical Dimensions Score-change at V11 n=52
    4.2 ± 12
        Psychological Dimensions Score-V3 n=57
    57.9 ± 19.3
        Psychological Dimensions Score-change at V11 n=52
    1.3 ± 10.4
        Appearance Sub-Dimension Score-V3 n=57
    46.9 ± 23.1
        Appearance Sub-Dimension Score-change at V11 n=52
    3.8 ± 13
        Personal Relnship Sub-Dim Score-V3 n=57
    68.9 ± 20.3
        Personal Relnship Sub-Dim Score-change at V11 n=52
    -0.1 ± 12.7
    No statistical analyses for this end point

    Secondary: Serum IGF-1 level (expressed as z-scores)

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    End point title
    		 Serum IGF-1 level (expressed as z-scores)
    End point description
    ITT population
    End point type
    Secondary
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months)
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: z-scores
    arithmetic mean (standard deviation)
        Visit 3 (n=57)
    6.49 ± 4.11
        Change at visit 11 (n=52)
    -4.5 ± 4.01
    No statistical analyses for this end point

    Secondary: Correlation between the change in quality of life and the change in z-score of IGF-1 level

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    End point title
    		 Correlation between the change in quality of life and the change in z-score of IGF-1 level
    End point description
    ITT population A decrease in IGF-1 z-score represents an improvement and an increase in ACROQoL score represents an improvement. Appearance and personal Relationships are Psychological Sub-Dimension. The values reported are Spearman's rank correlation (r) values
    End point type
    Secondary
    End point timeframe
    At visit 2, visit 3 and visit 11.
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: nanogram(s)
    number (not applicable)
        Change From V2 To V3 - Global Score
    -0.16
        Change From V2 To V3 - Physical Dimension
    -0.17
        Change From V2 To V3 - Psychological Dimension
    -0.1
        Change From V2 To V3 - Appearance
    -0.12
        Change From V2 To V3 - Personal Relationships
    -0.01
        Change From V3 To V11 - Global Score
    0.09
        Change From V3 To V11 - Physical Dimension
    0.14
        Change From V3 To V11 - Psychological Dimension
    0.08
        Change From V3 To V11 - Appearance
    0.04
        Change From V3 To V11 - Personal Relationships
    0.02
    No statistical analyses for this end point

    Secondary: The percentage of subjects with Serum IGF-1 Normalisation at Each Visit

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    End point title
    		 The percentage of subjects with Serum IGF-1 Normalisation at Each Visit
    End point description
    ITT population
    End point type
    Secondary
    End point timeframe
    At visit 1, 2, 3, 5, 7, 9 and 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Percentage of subjects
    number (not applicable)
        Visit 1 (n= 10)
    17.5
        Visit 2 (n= 13)
    24.5
        Visit 3 (n= 0)
    0
        Visit 5 (n= 31)
    56.4
        Visit 7 (n= 26)
    48.1
        Visit 9 (n= 30)
    57.7
        Visit 11 (n= 32)
    61.5
    No statistical analyses for this end point

    Other pre-specified: Changes in Mean Weight from Baseline

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    End point title
    		 Changes in Mean Weight from Baseline
    End point description
    The safety population is defined as all subjects who received at least one dose of each Investigational medicinal product (i.e. one dose of Lanreotide autogel 120 mg and one dose of Pegvisomant during the co-administration period).
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months)
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Kg
    arithmetic mean (standard deviation)
        Visit 3 (n= 55)
    87.3 ± 19.6
        Change at visit 11 (n= 49)
    -0.3 ± 2.9
    No statistical analyses for this end point

    Other pre-specified: Changes in Mean Supine Systolic BP from Baseline

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    End point title
    		 Changes in Mean Supine Systolic BP from Baseline
    End point description
    The safety population is defined as all subjects who received at least one dose of each Investigational medicinal product (i.e. one dose of Lanreotide autogel 120 mg and one dose of Pegvisomant during the co-administration period).
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months)
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: mmHg
    arithmetic mean (standard deviation)
        Visit 3 (n= 57)
    130.1 ± 13.6
        Change at visit 11 (n= 52)
    -0.4 ± 17.1
    No statistical analyses for this end point

    Other pre-specified: Changes in Mean Supine Diastolic BP from Baseline.

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    End point title
    		 Changes in Mean Supine Diastolic BP from Baseline.
    End point description
    The safety population is defined as all subjects who received at least one dose of each Investigational medicinal product (i.e. one dose of Lanreotide autogel 120 mg and one dose of Pegvisomant during the co-administration period).
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months)
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: mmHg
    arithmetic mean (standard deviation)
        Visit 3 (n= 57)
    81.3 ± 9.5
        Change at visit 11 (n= 52)
    -0.1 ± 11.4
    No statistical analyses for this end point

    Other pre-specified: Changes in Mean Supine Heart Rate from Baseline

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    End point title
    		 Changes in Mean Supine Heart Rate from Baseline
    End point description
    The safety population is defined as all subjects who received at least one dose of each Investigational medicinal product (i.e. one dose of Lanreotide autogel 120 mg and one dose of Pegvisomant during the co-administration period).
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months)
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: bpm
    arithmetic mean (standard deviation)
        Visit 3 (n= 57)
    69.8 ± 10.3
        Change at visit 11 (n= 50)
    -3.1 ± 12.6
    No statistical analyses for this end point

    Other pre-specified: Changes in electrocardiogram (ECG) Mean Heart Rate from Baseline

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    End point title
    		 Changes in electrocardiogram (ECG) Mean Heart Rate from Baseline
    End point description
    The safety population is defined as all subjects who received at least one dose of each Investigational medicinal product (i.e. one dose of Lanreotide autogel 120 mg and one dose of Pegvisomant during the co-administration period).
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months)
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: bpm
    arithmetic mean (standard deviation)
        Visit 3 (n= 56)
    64.6 ± 11.2
        Change at visit 11 (n= 50)
    -2.8 ± 11
    No statistical analyses for this end point

    Other pre-specified: Changes in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTc Interval Fridericia from Baseline.

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    End point title
    		 Changes in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTc Interval Fridericia from Baseline.
    End point description
    The safety population is defined as all subjects who received at least one dose of each Investigational medicinal product (i.e. one dose of Lanreotide autogel 120 mg and one dose of Pegvisomant during the co-administration period).
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months).
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: ms
    arithmetic mean (standard deviation)
        PR Interval, Visit 3 (n=55)
    165.9 ± 21.1
        PR Interval, Change at visit 11 (n=48)
    1.1 ± 15.8
        QRS Interval, Visit 3 (n=56)
    101.7 ± 16.5
        QRS Interval, Change at visit 11 (n=50)
    0.1 ± 10.1
        QT Interval, Visit 3 (n=52)
    402 ± 33.4
        QT Interval, Change at visit 11 (n=45)
    4 ± 29.7
        RR Interval, Visit 3 (n=56)
    959 ± 175.7
        RR Interval, Change at visit 11 (n=50)
    34.7 ± 175.4
        QTc Interval Fridericia, Visit 3 (n=52)
    410.8 ± 25.7
        QTc Interval Fridericia, Change at visit 11 (n=45)
    -1.8 ± 16.9
    No statistical analyses for this end point

    Other pre-specified: Number of subjects with shift in presence/absence of Lithiasis and/or Sludge during co-administration

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    End point title
    		 Number of subjects with shift in presence/absence of Lithiasis and/or Sludge during co-administration
    End point description
    Safety population.
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 (Baseline) and visit 11 (7 months)
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Number of subjects
        Subjects developed Sludge
    3
        Subjects resolved Sludge
    5
        Subjects developed Lithiasis
    2
        Subjects resolved Lithiasis
    1
    No statistical analyses for this end point

    Other pre-specified: Change in Mean Pituitary tumour Size

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    End point title
    		 Change in Mean Pituitary tumour Size
    End point description
    Safety population
    End point type
    Other pre-specified
    End point timeframe
    At visit 2, visit 3 and visit 11.
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: mm^3
    arithmetic mean (standard deviation)
        Visit 3 (n=56)
    2966.7 ± 4519
        Change at visit 11 (n=49)
    2.4 ± 729.7
    No statistical analyses for this end point

    Other pre-specified: Change in mean Blood Glucose Cmax from Oral Glucose Tolerance Test (OGTT) for Non Diabetic subjects

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    End point title
    		 Change in mean Blood Glucose Cmax from Oral Glucose Tolerance Test (OGTT) for Non Diabetic subjects
    End point description
    Safety population
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 and visit 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    38
    Units: mmol/L
    arithmetic mean (standard deviation)
        Visit 3 (n=38)
    10.3 ± 2.28
        Change at visit 11 (N=34)
    0.53 ± 1.72
    No statistical analyses for this end point

    Other pre-specified: Change in Mean Fasting insulin During Co-administration in Non Diabetic Subjects

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    End point title
    		 Change in Mean Fasting insulin During Co-administration in Non Diabetic Subjects
    End point description
    Safety population
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 and visit 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    37
    Units: pmol/L
    arithmetic mean (standard deviation)
        At visit 3 (n=37)
    56.1 ± 28.4
        Change at visit 11 (n=32)
    -12.7 ± 41.5
    No statistical analyses for this end point

    Other pre-specified: Change in Mean Blood Glucose Fasting for Non Diabetic Subjects

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    End point title
    		 Change in Mean Blood Glucose Fasting for Non Diabetic Subjects
    End point description
    Safety population
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 and visit 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    37
    Units: mmol/L
    arithmetic mean (standard deviation)
        At visit 3 (n=37)
    5.42 ± 0.59
        Change at visit 11 (n=32)
    -0.05 ± 0.71
    No statistical analyses for this end point

    Other pre-specified: Change in Mean Fasting Insulin / Glucose Ratio for Non Diabetic Subjects

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    End point title
    		 Change in Mean Fasting Insulin / Glucose Ratio for Non Diabetic Subjects
    End point description
    Safety population
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 and visit 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    36
    Units: N/A
    arithmetic mean (standard deviation)
        At visit 3 (n=36)
    10.66 ± 5.97
        Change at visit 11 (n=30)
    -2.61 ± 8.12
    No statistical analyses for this end point

    Other pre-specified: Change in Mean HbA1C

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    End point title
    		 Change in Mean HbA1C
    End point description
    Safety population HbA1C - Glycosylated Haemoglobin
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 and visit 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Percentage
    arithmetic mean (standard deviation)
        Diabetic Subjects at visit 3 (n=19)
    7 ± 1.26
        Diabetic Subjects Change at visit 11 (n=18)
    -0.05 ± 0.71
        Non Diabetic Subjects at visit 3 (n=38)
    5.88 ± 0.32
        Non Diabetic Subjects Change at visit 11 (n=33)
    0.05 ± 0.2
    No statistical analyses for this end point

    Other pre-specified: Laboratory tests - Changes in Liver Function Test Parameters

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    End point title
    		 Laboratory tests - Changes in Liver Function Test Parameters
    End point description
    Safety population
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 and visit 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: IU/L
    arithmetic mean (standard deviation)
        Aspartate Amino Transferase at visit 3 (n=57)
    17.8 ± 6.4
        Aspartate Amino Transferase change at V11 (n=52)
    3.3 ± 10.7
        Alanine Amino Transferase at visit 3 (n=57)
    15.1 ± 5.4
        Alanine Amino Transferase change at visit 11(n=52)
    4.1 ± 11.7
        Gamma Glutamyl Transferase at visit 3 (n=57)
    24.5 ± 31.7
        Gamma Glutamyl Transferase change at V11(n=52)
    -1 ± 17.8
        Alkaline Phosphatase at visit 3 (n=57)
    73.2 ± 33.9
        Alkaline Phosphatase change at visit 11 (n=52)
    -1.7 ± 14.5
    No statistical analyses for this end point

    Other pre-specified: Changes in Liver Function Test - Total Bilirubin

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    End point title
    		 Changes in Liver Function Test - Total Bilirubin
    End point description
    Safety population
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 and visit 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: μmol/L
    arithmetic mean (standard deviation)
        At visit 3 (n=57)
    8.3 ± 4.2
        Change at visit 11 (n=52)
    -1.3 ± 2.9
    No statistical analyses for this end point

    Other pre-specified: Changes in Liver Function Test - Prothrombin Level

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    End point title
    		 Changes in Liver Function Test - Prothrombin Level
    End point description
    Safety population
    End point type
    Other pre-specified
    End point timeframe
    At visit 3 and visit 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: percent
    arithmetic mean (standard deviation)
        At visit 3 (n=57)
    92.4 ± 12.8
        Change at visit 11 (n=51)
    -3.7 ± 16
    No statistical analyses for this end point

    Other pre-specified: Analyses for putative antibodies during the co-administration period

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    End point title
    		 Analyses for putative antibodies during the co-administration period
    End point description
    Safety population
    End point type
    Other pre-specified
    End point timeframe
    At visit 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Number of subjects
        Antibodies for Lanreotide
    4
        Antibodies for Pegvisomant
    6
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects with Adverse Events

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    End point title
    		 Number of Subjects with Adverse Events
    End point description
    ITT population AE (Adverse Event) TEAE (Treatment Emergent Adverse Event) SAE (Serious Adverse Event)
    End point type
    Other pre-specified
    End point timeframe
    Up to visit 11
    End point values
    		 Titration Basis
    Number of subjects analysed
    57
    Units: Number of subjects
        Run-in: Any AE
    33
        Run-in: Any TEAE
    30
        Run-in: Any severe TEAE
    2
        Run-in: Any severe treatment related TEAE
    0
        Run-in: Any SAE
    2
        Run-in: Any AE leading to withdrawal
    0
        Run-in: Any AE leading to death
    0
        Co-administration: Any AE
    44
        Co-administration: Any TEAE
    41
        Co-administration: Any severe TEAE
    7
        Coadministration:Any severe treatment related TEAE
    2
        Co-administration: Any SAE
    8
        Co-administration: Any AE leading to withdrawal
    5
        Co-administration: Any AE leading to death
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to visit 11.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Run-in period
    Reporting group description
    		 -

    Reporting group title
    Co-administration period
    Reporting group description
    		 -

    Serious adverse events
    		 Run-in period Co-administration period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 57 (3.51%)
    8 / 57 (14.04%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin cancer
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial palsy
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         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
    Thrombocytopenia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocortical insufficiency acute
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Wound infection
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Run-in period Co-administration period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 57 (50.88%)
    33 / 57 (57.89%)
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 57 (1.75%)
         occurrences all number
    1
    1
    Hypotension
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Orthostatic hypotension
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Venous insufficiency
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Application site induration
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Application site pain
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Injection site nodule
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 57 (3.51%)
         occurrences all number
    1
    2
    Injection site pain
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 57 (0.00%)
         occurrences all number
    2
    0
    Fatigue
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Injection site bruising
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    10
    Injection site erythema
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    0
    4
    Injection site haemorrhage
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Injection site rash
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Injection site swelling
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Oligomenorrhoea
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 57 (1.75%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 57 (1.75%)
         occurrences all number
    1
    1
    Nasal congestion
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Pharyngolaryngeal pain
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 57 (1.75%)
         occurrences all number
    2
    1
    Anxiety
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Investigations
    Blood prolactin increased
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Smear cervix abnormal
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Foot fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Intervertebral disc injury
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Cardiac disorders
    bradycardia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 57 (1.75%)
         occurrences all number
    2
    1
    Paraesthesia
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    0
    2
    Radiculopathy
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Macrocytosis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Abdominal rigidity
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    3
    0
    Constipation
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    5 / 57 (8.77%)
    4 / 57 (7.02%)
         occurrences all number
    12
    7
    Dyspepsia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 57 (1.75%)
         occurrences all number
    2
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Abdominal distension
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    0
    2
    Hepatobiliary disorders
    Gallbladder polyp
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Cytolytic hepatitis
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 57 (7.02%)
         occurrences all number
    0
    4
    Hepatotoxicity
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Cholelithiasis
         subjects affected / exposed
    6 / 57 (10.53%)
    2 / 57 (3.51%)
         occurrences all number
    7
    3
    Skin and subcutaneous tissue disorders
    Night sweats
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Blood blister
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Lipodystrophy acquired
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    0
    2
    Lipohypertrophy
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    0
    2
    RASH
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Hypothyroidism
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 57 (3.51%)
         occurrences all number
    1
    2
    Bone pain
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 57 (0.00%)
         occurrences all number
    2
    0
    Myalgia
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 57 (1.75%)
         occurrences all number
    2
    1
    Pain in extremity
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 57 (1.75%)
         occurrences all number
    1
    1
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 57 (1.75%)
         occurrences all number
    1
    1
    Bone cyst
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    0
    2
    Infections and infestations
    Influenza
         subjects affected / exposed
    3 / 57 (5.26%)
    4 / 57 (7.02%)
         occurrences all number
    3
    4
    Nasopharyngitis
         subjects affected / exposed
    2 / 57 (3.51%)
    5 / 57 (8.77%)
         occurrences all number
    2
    6
    Gastroenteritis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    4 / 57 (7.02%)
    2 / 57 (3.51%)
         occurrences all number
    4
    2
    Diabetes mellitus non insulin dependent
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Glucose tolerance impaired
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Fluid retention
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Feb 2007
    Protocol amendment 1 was issued primarily to change the proportion of subjects treated by pegvisomant and somatostatin analogues at study entry. The restriction that 50% of subjects should be previously treated with daily pegvisomant, and 50% should previously be treated with a somatostatin analogue (25% with lanreotide Autogel, 25% with octreotide LAR) was removed in order to improve recruitment into the study. Currently about 4% of patients with acromegaly receive daily treatment with pegvisomant across Europe. Aiming to have a fixed percentage of subjects previously treated by pegvisomant (that is 30 evaluable subjects) is not realistic considering the current therapeutic regimen of patients with acromegaly. In addition the criteria for hepatic toxicity was modified from Aspartate Amino Transferase (AST), Alanine Amino Transferase (ALT), Gamma Glutamyl Transferase (GGT), Alkaline Phosphatase (ALP), prothrombin time or total bilirubin > 2 x Upper Limit of Normal (ULN) to AST or ALT, > 2 x ULN; the number of participating sites was increased from 25 to 30; and the protocol was modified for the use of paper CRFs instead of electronic data capture (EDC).
    24 Jun 2008
    Protocol amendment 2 was issued to include a sensitivity analysis of the primary efficacy endpoint as an additional secondary endpoint. This additional endpoint assessed the correlation between changes in QoL with corresponding changes in z-score for IGF-1 levels. In addition protocol amendment 2 detailed the change in the location of analysis for lanreotide Autogel serum concentrations from Ipsen Pharma S.A. to SGS Cephac Europe.

    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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