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    Clinical Trial Results:
    A randomized placebo-controlled study in patients with a Gallium-68 DOTATATE PET/CT positive, clinically non-functioning pituitary macroadenoma (NFMA) of the effect of Lanreotide autosolution on Tumor (adenoma) size

    Summary
    EudraCT number
    		 2015-001234-22
    Trial protocol
    		 NL  
    Global end of trial date
    26 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Feb 2025
    First version publication date
    07 Feb 2025
    Other versions
    Summary report(s)
    		 Trial publication in The Lancet Regional Health - Europe

    Trial information

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    Trial identification
    Sponsor protocol code
    NL52821.018.15
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Nederlands Trial Register: NTR5275, National Trial Register (new): NL5136
    Sponsors
    Sponsor organisation name
    Academic Medical Center
    Sponsor organisation address
    Meibergdreef 9, Amsterdam, Netherlands, 1105 AZ
    Public contact
    Eric Fliers, principal investigator, Academic Medical Center (currently part of Amsterdam UMC), 0031 205666071, e.fliers@amsterdamumc.nl
    Scientific contact
    Eric Fliers, principal investigator, Academic Medical Center (currently part of Amsterdam UMC), 0031 205666071, e.fliers@amsterdamumc.nl
    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
    28 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of lanreotide autosolution during 72 weeks, as compared to placebo, on tumour size in patients with a non-functioning pituitary macroadenoma and positive pituitary somatostatin receptor imaging using Gallium-68 DOTATATE PET/CT. Note that our planned number of subjects was 66, as the percentage of positive Gallium-68 DOTATATE uptake was unknown and only those with positive uptake would be randomized for treatment. The final number of enrolled patients was 49 in order to be able to randomize 44 subjects between lanreotide and placebo.
    Protection of trial subjects
    The study was approved by the ethics committe and conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. All trial subjects were informed in full on the trial details, and received information in writing before providing informed consent. Privacy rules regarding collection and storing of medical and personal data were adhered to. Insurance was in place in case of damage caused by participation in the study. Trial subjects could withdraw from the study at any time and for any reason. All adverse events were recorded and followed up, and if necessary, subjects were withdrawn for medical reasons.
    Background therapy
    		 Subjects who had undergone previous adenoma surgery were eligible for inclusion, as long as the tumour remnant was >1cm in size.
    Evidence for comparator
    		 The comparator in our study is placebo.
    Actual start date of recruitment
    03 Nov 2015
    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: 49
    Worldwide total number of subjects
    49
    EEA total number of subjects
    49
    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)
    31
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place between 3 November 2015 and 10 December 2019. The study was conducted in an outpatient setting and eligible patients were referred by endocrinologists at academic and non-academic hospitals in the Netherlands for inclusion at one of the participating centres.

    Pre-assignment
    Screening details
    		 After inclusion and informed consent, all participants underwent the study 68Ga-DOTATATE PET-CT. Only those participants with positive tracer uptake within the adenoma were randomised for study treatment.

    Pre-assignment period milestones
    Number of subjects started
    		 49
    Intermediate milestone: Number of subjects
    68Ga-DOTATATE PET-CT scan: 49
    Number of subjects completed
    		 44

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Physician decision: 1
    Reason: Number of subjects
    		 negative 68Ga-DOTATATE PET: 4
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    The randomisation list was stored in a secure trial file at the Pharmacy and was only disclosed after database lock. As the prefilled lanreotide syringes differed in appearance from the placebo, injections were administered by trained, independent nurses who were unmasked to treatment allocation, a method also used in previous trials. To maintain blinding during transport, prepared study medication was placed in an opaque bag within a sealed cardboard box.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lanreotide
    Arm description
    		 Treatment with lanreotide acetate 120mg (Somatuline AutoSolution, Ipsen Farmaceutica BV; known outside the Netherlands as Somatuline Autogel), without dose titration.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Somatuline Autosolution
    Investigational medicinal product code
    PR1
    Other name
    lanreotide acetate, Somatuline Autogel
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use, Solution for injection
    Dosage and administration details
    Pre-filled syringes with dosage of 120mg (volume 0.4mL), administered every 28 days as a deep subcutaneous injection into the superior, external quadrant of the buttock.

    Arm title
    		 Placebo
    Arm description
    		 Treatment with placebo, consisting of saline 0.9%
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    saline 0.9%
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Solution for injection , Subcutaneous use
    Dosage and administration details
    Solution of saline (sodium chloride 0.9%), delivered in plastic bottle with syringe and needle. Trained nurses drew up 0.4 mL (matching the Somatuline Autosolution volume) to prepare the injection for administration. Injections were administered every 28 days as a deep subcutaneous injection into the superior, external quadrant of the buttock.

    Number of subjects in period 1 [1]
    		Lanreotide Placebo
    Started
    22
    22
    24 week visit
    19
    22
    48 week visit
    16
    20
    Completed
    13
    19
    Not completed
    9
    3
         Adverse event, non-fatal
    4
    -
         Lack of efficacy
    3
    3
         Protocol deviation
    2
    -
    Notes
    [1] - 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: After inclusion and informed consent, all 49 participants underwent the study 68Ga-DOTATATE PET-CT. Only those participants with positive tracer uptake within the adenoma were randomised for study treatment and formed the overall trial (and are thus reported in the baseline period), this number is 44 as prespecified in the power calculation.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lanreotide
    Reporting group description
    		 Treatment with lanreotide acetate 120mg (Somatuline AutoSolution, Ipsen Farmaceutica BV; known outside the Netherlands as Somatuline Autogel), without dose titration.

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment with placebo, consisting of saline 0.9%

    Reporting group values
    		 Lanreotide Placebo Total
    Number of subjects
    		 22 22 44
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 15 11 26
        From 65-84 years
    		 7 11 18
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.8 ( 8.2 ) 63.5 ( 8.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 6 16
        Male
    		 12 16 28
    Any pituitary hormone deficiency
    Units: Subjects
        No
    		 7 11 18
        Yes
    		 15 11 26
    Previous NFPMA resection
    At any time before study participation. NFPMA = non-functioning pituitary macroadenoma
    Units: Subjects
        No
    		 7 13 20
        Yes
    		 15 9 24
    Centre of inclusion
    Units: Subjects
        Amsterdam UMC location AMC
    		 15 16 31
        Amsterdam UMC location VUmc
    		 1 3 4
        Leiden University Medical Centre (LUMC)
    		 6 3 9
    Baseline NFPMA cranio-caudal diameter
    NFPMA=non-functioning pituitary macroadenoma
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    		 16.2 (13.4 to 20.6) 16.3 (14.8 to 19.3) -
    Baseline NFPMA tumour volume
    NFPMA = non-functioning pituitary macroadenoma
    Units: cubic millimeter
        median (inter-quartile range (Q1-Q3))
    		 2782 (1868 to 4067) 2722 (1937 to 3967) -
    68Ga-DOTATATE PET NFPMA SUVmean
    The mean standard uptake value measured within the adenoma. SUV is an unitless value. NFPMA=non-functioning pituitary macroadenoma. PET=positron emission tomography. SUV=standard uptake value.
    Units: unit(s)
        median (inter-quartile range (Q1-Q3))
    		 6.1 (3.2 to 8.1) 5.0 (2.7 to 6.7) -
    68Ga-DOTATATE PET NFPMA SUVmax
    The maximum standard uptake value measured within the adenoma. SUV is a unitless value. NFPMA=non-functioning pituitary macroadenoma. PET=positron emission tomography. SUV=standard uptake value.
    Units: unit(s)
        median (inter-quartile range (Q1-Q3))
    		 7.9 (5.0 to 11.0) 6.4 (3.5 to 9.1) -
    Subject analysis sets

    Subject analysis set title
    All included participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Clinical characteristics of all participants with 68Ga-DOTATATE PET-positive and PET-negative adenoma. Only PET-positive participants were randomised to study treatment. Note: there is no centrally assessed baseline or end tumour size (cranio-caudal diameter and tumour volume) data for this subject analysis set.

    Subject analysis set title
    Per-protocol population - lanreotide group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol population included participants who completed study treatment with all 18 injections and underwent week-72 MRI (deviations in visit time windows were allowed). This set comprises participants in the lanreotide group who completed the study (n=13).

    Subject analysis set title
    Per-protocol population - placebo group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol population included participants who completed study treatment with all 18 injections and underwent week-72 MRI (deviations in visit time windows were allowed). This set comprises participants in the placebo group who completed the study (n=19).

    Subject analysis sets values
    		 All included participants Per-protocol population - lanreotide group Per-protocol population - placebo group
    Number of subjects
    49
    13
    19
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    31
        From 65-84 years
    18
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.3 ( 10.2 )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    18
        Male
    31
    Any pituitary hormone deficiency
    Units: Subjects
        No
    20
        Yes
    29
    Previous NFPMA resection
    At any time before study participation. NFPMA = non-functioning pituitary macroadenoma
    Units: Subjects
        No
    23
        Yes
    26
    Centre of inclusion
    Units: Subjects
        Amsterdam UMC location AMC
    34
        Amsterdam UMC location VUmc
    5
        Leiden University Medical Centre (LUMC)
    10
    Baseline NFPMA cranio-caudal diameter
    NFPMA=non-functioning pituitary macroadenoma
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    Baseline NFPMA tumour volume
    NFPMA = non-functioning pituitary macroadenoma
    Units: cubic millimeter
        median (inter-quartile range (Q1-Q3))
    68Ga-DOTATATE PET NFPMA SUVmean
    The mean standard uptake value measured within the adenoma. SUV is an unitless value. NFPMA=non-functioning pituitary macroadenoma. PET=positron emission tomography. SUV=standard uptake value.
    Units: unit(s)
        median (inter-quartile range (Q1-Q3))
    5.4 (2.9 to 7.2)
    68Ga-DOTATATE PET NFPMA SUVmax
    The maximum standard uptake value measured within the adenoma. SUV is a unitless value. NFPMA=non-functioning pituitary macroadenoma. PET=positron emission tomography. SUV=standard uptake value.
    Units: unit(s)
        median (inter-quartile range (Q1-Q3))
    7.0 (3.5 to 9.6)

    End points

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    End points reporting groups
    Reporting group title
    Lanreotide
    Reporting group description
    		 Treatment with lanreotide acetate 120mg (Somatuline AutoSolution, Ipsen Farmaceutica BV; known outside the Netherlands as Somatuline Autogel), without dose titration.

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment with placebo, consisting of saline 0.9%

    Subject analysis set title
    All included participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Clinical characteristics of all participants with 68Ga-DOTATATE PET-positive and PET-negative adenoma. Only PET-positive participants were randomised to study treatment. Note: there is no centrally assessed baseline or end tumour size (cranio-caudal diameter and tumour volume) data for this subject analysis set.

    Subject analysis set title
    Per-protocol population - lanreotide group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol population included participants who completed study treatment with all 18 injections and underwent week-72 MRI (deviations in visit time windows were allowed). This set comprises participants in the lanreotide group who completed the study (n=13).

    Subject analysis set title
    Per-protocol population - placebo group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol population included participants who completed study treatment with all 18 injections and underwent week-72 MRI (deviations in visit time windows were allowed). This set comprises participants in the placebo group who completed the study (n=19).

    Primary: Change in cranio-caudal diameter

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    End point title
    		 Change in cranio-caudal diameter
    End point description
    End point type
    Primary
    End point timeframe
    Primary outcome was the change in cranio-caudal tumour diameter from baseline to week-72 or treatment discontinuation.
    End point values
    		 Lanreotide Placebo Per-protocol population - lanreotide group Per-protocol population - placebo group
    Number of subjects analysed
    22
    22
    13
    19
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    1.2 ( 2.5 )
    1.3 ( 1.5 )
    1.3 ( 3.0 )
    1.2 ( 1.6 )
    Attachments
    		 Primary outcome main, additional & sensitivity ana
    Change in tumour size from baseline to end-of-trea
    Primary&secondary tumour size outcomes in ITT & PP
    Statistical analysis title
    		 Primary outcome main analysis (ITT population)
    Statistical analysis description
    For the main analysis of the primary outcome change in cranio-caudal diameter, all data up to treatment discontinuation was included (ie, ‘while-on-treatment’ strategy). An analysis of covariance (ANCOVA) model was used to control for any chance imbalance in baseline size between groups, with end-of-treatment measurement as dependent variable, baseline measurement as continuous covariate, and treatment as categorical covariate.
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.93 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6
    Notes
    [1] - The statistical significance level for analyses was set at p = 0·05 (two-sided). There was no need for multiplicity adjustments.
    Statistical analysis title
    		 Primary outcome in per-protocol population
    Statistical analysis description
    For the analysis of the primary outcome change in cranio-caudal diameter in the per-protocol population an analysis of covariance (ANCOVA) model was used to control for any chance imbalance in baseline size between groups, with end-of-treatment measurement as dependent variable, baseline measurement as continuous covariate, and treatment as categorical covariate.
    Comparison groups
    Per-protocol population - placebo group v Per-protocol population - lanreotide group
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8
    Statistical analysis title
    		 Primary outcome multiple imputation missing data
    Statistical analysis description
    A supplementary efficacy analysis applied univariate multiple imputation to impute missing week-72 MRI data, assuming missingness at random (MAR). Data were imputed separately in each treatment group using a regression model, and 27 imputed datasets were generated (corresponding to 27% of missing week-72 data). Each dataset was assessed with the earlier specified ANCOVA model and results were pooled using Rubin’s rules.
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.25
         upper limit
    		 1.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.82
    Statistical analysis title
    		 Pattern-mixture model (sensitivity), δ= +0.317mm
    Statistical analysis description
    Sensitivity analysis via pattern-mixture model to explore departures from missing-at-random (MAR) assumption and address potential bias due to differential dropout between treatment groups. The imputed MAR data was shifted by a range of offsets (δ, delta) to assess alternative post-dropout scenarios of tumour behaviour. Results under MAR were considered robust if an observed treatment effect was qualitatively maintained for a range of plausible offsets.
    Comparison groups
    Placebo v Lanreotide
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.16
         upper limit
    		 2.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.83
    Statistical analysis title
    		 Pattern-mixture model (sensitivity), δ= +0.634mm
    Statistical analysis description
    Sensitivity analysis via pattern-mixture model to explore departures from missing-at-random (MAR) assumption and address potential bias due to differential dropout between treatment groups. The imputed MAR data was shifted by a range of offsets (δ, delta) to assess alternative post-dropout scenarios of tumour behaviour. Results under MAR were considered robust if an observed treatment effect was qualitatively maintained for a range of plausible offsets.
    Comparison groups
    Placebo v Lanreotide
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.09
         upper limit
    		 2.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.83
    Statistical analysis title
    		 Pattern-mixture model (sensitivity), δ= +0.950mm
    Statistical analysis description
    Sensitivity analysis via pattern-mixture model to explore departures from missing-at-random (MAR) assumption and address potential bias due to differential dropout between treatment groups. The imputed MAR data was shifted by a range of offsets (δ, delta) to assess alternative post-dropout scenarios of tumour behaviour. Results under MAR were considered robust if an observed treatment effect was qualitatively maintained for a range of plausible offsets.
    Comparison groups
    Placebo v Lanreotide
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 2.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.84
    Statistical analysis title
    		 Pattern-mixture model (sensitivity), δ= +1.267mm
    Statistical analysis description
    Sensitivity analysis via pattern-mixture model to explore departures from missing-at-random (MAR) assumption and address potential bias due to differential dropout between treatment groups. The imputed MAR data was shifted by a range of offsets (δ, delta) to assess alternative post-dropout scenarios of tumour behaviour. Results under MAR were considered robust if an observed treatment effect was qualitatively maintained for a range of plausible offsets.
    Comparison groups
    Placebo v Lanreotide
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.39
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 2.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.85
    Statistical analysis title
    		 Pattern-mixture model (sensitivity), δ= +2.534mm
    Statistical analysis description
    Sensitivity analysis via pattern-mixture model to explore departures from missing-at-random (MAR) assumption and address potential bias due to differential dropout between treatment groups. The imputed MAR data was shifted by a range of offsets (δ, delta) to assess alternative post-dropout scenarios of tumour behaviour. Results under MAR were considered robust if an observed treatment effect was qualitatively maintained for a range of plausible offsets.
    Comparison groups
    Placebo v Lanreotide
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.68
         upper limit
    		 2.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.91
    Statistical analysis title
    		 Tipping point analysis, δ= -5.385mm for lanreotide
    Statistical analysis description
    A tipping-point analysis explored which δ-shift was needed to overturn the conclusion of the main analysis (ie, in which alternative post-dropout scenario would treatment effect be statistically significant). This involved subtracting increasing percentages of the mean change from the MAR imputed data in the lanreotide group until the resulting treatment effect following ANCOVA was statistically significant. The required δ of -5.385mm was considered clinically highly implausible.
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.002
         upper limit
    		 3.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.96
    Statistical analysis title
    		 Linear mixed effects model
    Statistical analysis description
    Linear mixed effects model to account for repeated MRI measurements obtained at varying time-points. Post-baseline cranio-caudal diameter was modelled with treatment group, measurement time, group‐by‐time interaction, baseline cranio-caudal diameter, and baseline diameter‐by‐time interaction as fixed effects, a by-subject random intercept, and a first-order autoregressive residual autocorrelation structure. Treatment effect was estimated as the contrast between adjusted group means at final time
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.82 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.29
         upper limit
    		 1.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58
    Notes
    [2] - The final model was modified post-hoc to include the additional fixed effects of baseline cranio-caudal diameter and baseline diameter‐by‐time interaction to correctly adjust for baseline size; the outcome/response vector was adjusted to only contain post-baseline measurements. As an additional post-hoc optimisation, a residual correlation matrix was specified to address possible residual serial autocorrelation not sufficiently accounted for by the random intercept.
    [3] - Treatment effect estimated as the contrast between treatment groups at final measurement time (corresponding to week-72) using R emmeans package, based on least‐square means with Satterthwaite method for approximation of degrees of freedom
    Statistical analysis title
    		 Mixed model for repeated measurements (MMRM)
    Statistical analysis description
    Data were fitted post-hoc with a MMRM to relax the LME assumption of linear time trends, with time as categorical variable and an unstructured covariance matrix to model within-patient residual errors. This required ‘simplification’ of post-baseline time data to a factor with only 4 levels: time1=measurement obtained before week-24 visit, time2=week-24 visit, time3=measurement obtained between week-24 and week-72 visit, and time4=week-72 (end) visit.
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.92 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 1.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.75
    Notes
    [4] - The model included the fixed effects of group, time, group‐by‐time interaction, baseline size, and baseline size‐by‐time interaction; and an unstructured covariance matrix to model within-patient residual errors.
    [5] - Treatment effect estimated as the contrast between treatment groups at end visit (corresponding to week-72) using R emmeans package, based on least‐square means with Satterthwaite method for approximation of degrees of freedom

    Secondary: Change in tumour volume

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    End point title
    		 Change in tumour volume
    End point description
    End point type
    Secondary
    End point timeframe
    The change in tumour volume from baseline to week-72 or treatment discontinuation.
    End point values
    		 Lanreotide Placebo Per-protocol population - lanreotide group Per-protocol population - placebo group
    Number of subjects analysed
    22
    22
    13
    19
    Units: cubic millimeter
        median (inter-quartile range (Q1-Q3))
    424 (61 to 811)
    181 (19 to 738)
    590 (91 to 828)
    260 (26 to 1049)
    Statistical analysis title
    		 Tumour volume main analysis (ITT population)
    Statistical analysis description
    For the main analysis of the secondary outcome change in tumour volume, all data up to treatment discontinuation was included (ie, ‘while-on-treatment’ strategy). An analysis of covariance (ANCOVA) model was used to control for any chance imbalance in baseline size between groups, with end-of-treatment measurement as dependent variable, baseline measurement as continuous covariate, and treatment as categorical covariate.
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -422
         upper limit
    		 486
    Notes
    [6] - Tumour volume values were natural log-transformed before analysis due to non-normal distribution with moderate positive skewness, the back-transformed estimated mean difference and 95% CI are reported.
    Statistical analysis title
    		 Tumour volume per-protocol population
    Statistical analysis description
    For the analysis of the secondary outcome change in tumour volume in the per-protocol population an analysis of covariance (ANCOVA) model was used to control for any chance imbalance in baseline size between groups, with end-of-treatment measurement as dependent variable, baseline measurement as continuous covariate, and treatment as categorical covariate.
    Comparison groups
    Per-protocol population - lanreotide group v Per-protocol population - placebo group
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -657
         upper limit
    		 706
    Variability estimate
    Standard error of the mean
    Dispersion value
    333
    Notes
    [7] - Tumour volume values in the per-protocol population were sufficiently normally distributed and thus not (natural log) transformed for analysis.

    Secondary: Time to tumour volume progression

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    End point title
    		 Time to tumour volume progression
    End point description
    Tumour progression was defined as clinically significant increase in tumour volume of ≥20%.
    End point type
    Secondary
    End point timeframe
    Time to progression was defined as the interval in weeks between start of study treatment and the first subsequent MRI scan showing a clinically significant increase in tumour volume, counting events in each group.
    End point values
    		 Lanreotide Placebo
    Number of subjects analysed
    22
    22
    Units: events
    9
    5
    Attachments
    		 Kaplan-Meier estimates of time to tumour progressi
    Statistical analysis title
    		 Time to progression in tumour volume
    Statistical analysis description
    Time to progression compared between groups with stratified log-rank test, with stratification for presence or absence of documented tumour growth at baseline. Hazard ratio derived from a Cox proportional-hazards model with terms for study treatment and tumour growth at baseline; with no statistically significant interaction between these terms. There were 9 events in placebo group (median time to progression 72 wks, 95% CI not reached), and 5 events in placebo group (median time not reached).
    Comparison groups
    Placebo v Lanreotide
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11 [8]
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 7.15
    Notes
    [8] - Stratified log-rank test, with stratification for presence or absence of documented tumour growth at baseline.

    Secondary: Change in SF-36 component score physical functioning

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    End point title
    		 Change in SF-36 component score physical functioning
    End point description
    End point type
    Secondary
    End point timeframe
    The change in quality of life based on SF-36 component score physical functioning (PF) from baseline to week-72 or treatment discontinuation. The scores are converted to 0-100 unitless scale.
    End point values
    		 Lanreotide Placebo
    Number of subjects analysed
    22
    22
    Units: unit(s)
        arithmetic mean (standard deviation)
    -0.4 ( 16.1 )
    -5.5 ( 16.1 )
    Attachments
    		 Spider plots of mean SF-36 component scores
    Change in SF-36 component scores
    Statistical analysis title
    		 Change in SF-36 physical functioning
    Statistical analysis description
    Change from baseline in component scores was compared between groups using ANCOVA with end-of-treatment score as dependent variable, baseline score as continuous covariate, and treatment as categorical covariate. The mean imputation method was used to replace missing component score values up to treatment discontinuation.
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.7
         upper limit
    		 14.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.2

    Secondary: Change in SF-36 component score limitations physical health

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    End point title
    		 Change in SF-36 component score limitations physical health
    End point description
    End point type
    Secondary
    End point timeframe
    The change in quality of life based on SF-36 component score role limitations due to physical health problems (RP) from baseline to week-72 or treatment discontinuation. The scores are converted to 0-100 unitless scale.
    End point values
    		 Lanreotide Placebo
    Number of subjects analysed
    22
    22
    Units: unit(s)
        arithmetic mean (standard deviation)
    -12.0 ( 26.9 )
    -4.8 ( 36.5 )
    Statistical analysis title
    		 Change in SF-36 limitations physical
    Statistical analysis description
    Change from baseline in component scores was compared between groups using ANCOVA with end-of-treatment score as dependent variable, baseline score as continuous covariate, and treatment as categorical covariate. The mean imputation method was used to replace missing component score values up to treatment discontinuation.
    Comparison groups
    Placebo v Lanreotide
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -9.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.2
         upper limit
    		 9.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.4

    Secondary: Change in SF-36 component score bodily pain

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    End point title
    		 Change in SF-36 component score bodily pain
    End point description
    End point type
    Secondary
    End point timeframe
    The change in quality of life based on SF-36 component score bodily pain (BP) from baseline to week-72 or treatment discontinuation. The scores are converted to 0-100 unitless scale.
    End point values
    		 Lanreotide Placebo
    Number of subjects analysed
    22
    22
    Units: unit(s)
        arithmetic mean (standard deviation)
    -8.5 ( 26.1 )
    -2.9 ( 13.7 )
    Statistical analysis title
    		 Change in SF-36 bodily pain
    Statistical analysis description
    Change from baseline in component scores was compared between groups using ANCOVA with end-of-treatment score as dependent variable, baseline score as continuous covariate, and treatment as categorical covariate. The mean imputation method was used to replace missing component score values up to treatment discontinuation.
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.29
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19
         upper limit
    		 5.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.1

    Secondary: Change in SF-36 component score general health

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    End point title
    		 Change in SF-36 component score general health
    End point description
    End point type
    Secondary
    End point timeframe
    The change in quality of life based on SF-36 component score general health perceptions (GH) from baseline to week-72 or treatment discontinuation. The scores are converted to 0-100 unitless scale.
    End point values
    		 Lanreotide Placebo
    Number of subjects analysed
    22
    22
    Units: unit(s)
        arithmetic mean (standard deviation)
    -1.6 ( 13.7 )
    -1.1 ( 12.0 )
    Statistical analysis title
    		 Change in SF-36 general health
    Statistical analysis description
    Change from baseline in component scores was compared between groups using ANCOVA with end-of-treatment score as dependent variable, baseline score as continuous covariate, and treatment as categorical covariate. The mean imputation method was used to replace missing component score values up to treatment discontinuation.
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.3
         upper limit
    		 7.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.1

    Secondary: Change in SF-36 component score vitality

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    End point title
    		 Change in SF-36 component score vitality
    End point description
    End point type
    Secondary
    End point timeframe
    The change in quality of life based on SF-36 component score vitality (VT) from baseline to week-72 or treatment discontinuation. The scores are converted to 0-100 unitless scale.
    End point values
    		 Lanreotide Placebo
    Number of subjects analysed
    22
    22
    Units: unit(s)
        arithmetic mean (standard deviation)
    -5.4 ( 17.3 )
    -0.9 ( 12.7 )
    Statistical analysis title
    		 Change in SF-36 vitality
    Statistical analysis description
    Change from baseline in component scores was compared between groups using ANCOVA with end-of-treatment score as dependent variable, baseline score as continuous covariate, and treatment as categorical covariate. The mean imputation method was used to replace missing component score values up to treatment discontinuation.
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.8
         upper limit
    		 2.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.6

    Secondary: Change in SF-36 component score social functioning

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    End point title
    		 Change in SF-36 component score social functioning
    End point description
    End point type
    Secondary
    End point timeframe
    The change in quality of life based on SF-36 component score social functioning (SF) from baseline to week-72 or treatment discontinuation. The scores are converted to 0-100 unitless scale.
    End point values
    		 Lanreotide Placebo
    Number of subjects analysed
    22
    22
    Units: unit(s)
        arithmetic mean (standard deviation)
    -5.6 ( 22.0 )
    -4.5 ( 14.2 )
    Statistical analysis title
    		 Change in SF-36 social functioning
    Statistical analysis description
    Change from baseline in component scores was compared between groups using ANCOVA with end-of-treatment score as dependent variable, baseline score as continuous covariate, and treatment as categorical covariate. The mean imputation method was used to replace missing component score values up to treatment discontinuation.
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.61
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.7
         upper limit
    		 8.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.8

    Secondary: Change in SF-36 component score limitations emotional

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    End point title
    		 Change in SF-36 component score limitations emotional
    End point description
    End point type
    Secondary
    End point timeframe
    The change in quality of life based on SF-36 component score role limitations due to emotional problems (RE) from baseline to week-72 or treatment discontinuation. The scores are converted to 0-100 unitless scale.
    End point values
    		 Lanreotide Placebo
    Number of subjects analysed
    22
    22
    Units: unit(s)
        arithmetic mean (standard deviation)
    -8.7 ( 30.9 )
    -6.1 ( 24.4 )
    Statistical analysis title
    		 Change in SF-36 limitations emotional
    Statistical analysis description
    Change from baseline in component scores was compared between groups using ANCOVA with end-of-treatment score as dependent variable, baseline score as continuous covariate, and treatment as categorical covariate. The mean imputation method was used to replace missing component score values up to treatment discontinuation
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.4
         upper limit
    		 10.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.5

    Secondary: Change in SF-36 component score general mental health

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    End point title
    		 Change in SF-36 component score general mental health
    End point description
    End point type
    Secondary
    End point timeframe
    The change in quality of life based on SF-36 component score general mental health (MH) from baseline to week-72 or treatment discontinuation. The scores are converted to 0-100 unitless scale.
    End point values
    		 Lanreotide Placebo
    Number of subjects analysed
    22
    22
    Units: unit(s)
        arithmetic mean (standard deviation)
    -4.9 ( 13.4 )
    0.2 ( 6.8 )
    Statistical analysis title
    		 Change in SF-36 general mental health
    Statistical analysis description
    Change from baseline in component scores was compared between groups using ANCOVA with end-of-treatment score as dependent variable, baseline score as continuous covariate, and treatment as categorical covariate. The mean imputation method was used to replace missing component score values up to treatment discontinuation.
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.9
         upper limit
    		 1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.3

    Other pre-specified: Tumour volume percentage change

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    End point title
    		 Tumour volume percentage change
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Percentage change in tumour volume from baseline measurement to week 72 or treatment discontinuation. No between-group analysis performed on this end point.
    End point values
    		 Lanreotide Placebo
    Number of subjects analysed
    22
    22
    Units: percent
        median (inter-quartile range (Q1-Q3))
    17.2 (1.5 to 29.7)
    7.8 (0.7 to 16.2)
    No statistical analyses for this end point

    Post-hoc: Time to tumour volume or cranio-caudal diameter progression

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    End point title
    		 Time to tumour volume or cranio-caudal diameter progression
    End point description
    Tumour progression was defined as clinically significant increase of either in tumour volume (≥20%) or cranio-caudal diameter (≥2 mm) on any subsequent MRI scan past baseline.
    End point type
    Post-hoc
    End point timeframe
    Time to progression was defined as the interval in weeks between start of study treatment and the first subsequent MRI scan showing a clinically significant increase in tumour volume or cranio-caudal diameter, counting events in each group.
    End point values
    		 Lanreotide Placebo
    Number of subjects analysed
    22
    22
    Units: events
    11
    9
    Attachments
    		 Kaplan-Meier estimates of time to tumour progressi
    Statistical analysis title
    		 Time to tumour progression
    Statistical analysis description
    Time to progression compared between groups with stratified log-rank test, with stratification for presence or absence of documented tumour growth at baseline. Hazard ratio derived from a Cox proportional-hazards model with terms for study treatment and tumour growth at baseline; with no statistically significant interaction between these terms. There were 11 events in lanreotide group (median time to progression 72 wks, 95% CI 50.6-83.4), and 9 events in placebo group (median time not reached).
    Comparison groups
    Lanreotide v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.25 [9]
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 4.15
    Notes
    [9] - Stratified log-rank test, with stratification for presence or absence of documented tumour growth at baseline.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any undesirable event, finding, or change from baseline (eg, worsening of known dyspepsia) occurring between study enrolment and up to 30 days after treatment completion or discontinuation was considered an adverse event.
    Adverse event reporting additional description
    AEs were assessed systematically at each study visit (via i.a. a fasting blood sample, measurement of vitals, and a semi-structured interview focused on AEs/side effects). Non-systematically assessed AEs (through self-reporting at any time during study participation) are not reported here, but have been published.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Lanreotide
    Reporting group description
    		 Treatment with lanreotide acetate 120mg (Somatuline AutoSolution, Ipsen Farmaceutica BV; known outside the Netherlands as Somatuline Autogel), without dose titration.

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment with placebo, consisting of saline 0.9%

    Serious adverse events
    		 Lanreotide Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 22 (27.27%)
    3 / 22 (13.64%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Hospital admission for observation after bike accident
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospital admission for planned adenoma resection
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospital admission for planned ileocecal resection due to complicated Crohn's disease
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hospital admission for analysis of chest pain and/or dyspnoea
    Additional description: Critical conditions such as pulmonary embolism or myocardial ischemia were ruled out.
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    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
    		 Lanreotide Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 22 (100.00%)
    21 / 22 (95.45%)
    Investigations
    Insulin-like growth factor decreased
    Additional description: Age-adjusted IGF-1 SDS below -2·0
         subjects affected / exposed
    4 / 22 (18.18%)
    0 / 22 (0.00%)
         occurrences all number
    4
    0
    Weight decreased
    Additional description: Unintentional weight loss
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Thyroxine free decreased
    Additional description: Free thyroxine below lower limit of normal
         subjects affected / exposed
    6 / 22 (27.27%)
    1 / 22 (4.55%)
         occurrences all number
    6
    1
    Liver function test increased
    Additional description: Comprising alanine aminotransferase or gamma-glutamyltransferase >2 times the upper limit of normal or alkaline phosphatase >20 U/L above the upper limit of normal
         subjects affected / exposed
    4 / 22 (18.18%)
    2 / 22 (9.09%)
         occurrences all number
    4
    2
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    22
    Cardiac disorders
    Bradycardia
    Additional description: defined as <60 beats per minute
         subjects affected / exposed
    4 / 22 (18.18%)
    0 / 22 (0.00%)
         occurrences all number
    4
    0
    Nervous system disorders
    Dizziness
    Additional description: Dizziness or light-headedness
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 22 (13.64%)
         occurrences all number
    2
    3
    Headache
         subjects affected / exposed
    7 / 22 (31.82%)
    4 / 22 (18.18%)
         occurrences all number
    7
    4
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    12 / 22 (54.55%)
    0 / 22 (0.00%)
         occurrences all number
    12
    0
    Fatigue
         subjects affected / exposed
    5 / 22 (22.73%)
    3 / 22 (13.64%)
         occurrences all number
    5
    3
    Eye disorders
    Visual impairment
    Additional description: Visual complaints or disturbances
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 22 (13.64%)
         occurrences all number
    3
    3
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Complaints of abdominal pain, discomfort, cramps
         subjects affected / exposed
    10 / 22 (45.45%)
    2 / 22 (9.09%)
         occurrences all number
    10
    2
    Frequent bowel movements
    Additional description: Increased stool frequency or diarrhoea
         subjects affected / exposed
    16 / 22 (72.73%)
    4 / 22 (18.18%)
         occurrences all number
    16
    4
    Nausea
    Additional description: nausea or dyspepsia
         subjects affected / exposed
    8 / 22 (36.36%)
    1 / 22 (4.55%)
         occurrences all number
    8
    1
    Decreased appetite
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Flatulence
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 22 (4.55%)
         occurrences all number
    3
    1
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: Any complaint of increased hair loss or decreased hair growth
         subjects affected / exposed
    5 / 22 (22.73%)
    0 / 22 (0.00%)
         occurrences all number
    5
    0
    Endocrine disorders
    Impaired fasting glucose
    Additional description: Defined as fasting glucose level of 5.7–6.9 mmol/L
         subjects affected / exposed
    10 / 22 (45.45%)
    3 / 22 (13.64%)
         occurrences all number
    10
    3
    Hyperglycaemia
    Additional description: Defined as glucose level ≥7 mmol/L
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 22 (9.09%)
         occurrences all number
    1
    2
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 22 (9.09%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2016
    - Leiden University Medical Centre added as participating centre to achieve target recruitment goal - Ability to perform the 68Ga-DOTATATE PET/CT at Amsterdam UMC location AMC - Possibility for participants to have study injections administered at home by trained nurses of a specialised homecare company (Eurocept Homecare).
    31 Aug 2017
    - Clearer definition of exclusion criterion concerning dopamine receptor agonist use: “Use of dopamine receptor agonists” was modified to “Use of dopamine receptor agonist in the past 6 months”. Inclusions up to this amendment were not affected by the modification.
    30 Nov 2018
    - Increased sample size to 22 participants per treatment group to account for an observed overall dropout rate of ~25%. - More detailed statistical analysis section.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/39070749
    http://www.ncbi.nlm.nih.gov/pubmed/32792446
    http://www.ncbi.nlm.nih.gov/pubmed/34191241
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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