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    Clinical Trial Results:
    Phase IIA, open label, dose ascending study to determine the maximum tolerated dose, safety and tolerability, pharmacokinetics and pharmacodynamics of a single dose of lanreotide prolonged release formulation in subjects with acromegaly previously treated and controlled with either ocreotide Long Acting Release or lanreotide Autogel.

    Summary
    EudraCT number
    		 2014-002389-62
    Trial protocol
    		 GB   BE   DE   NL   CZ   LT   ES   IT   PL  
    Global end of trial date
    28 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Nov 2018
    First version publication date
    09 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8-55-52030-309
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02396953
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ipsen
    Sponsor organisation address
    65 quai George Gorse, Boulogne Billancourt, France, 92100
    Public contact
    Medical Director, Ipsen, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Ipsen, 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
    28 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to identify the maximum tolerated dose (MTD) and to investigate the pharmacokinetics (PK) of a single dose of lanreotide prolonged release formulation (PRF) in subjects with acromegaly.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki in accordance with the International Council for Harmonisation Consolidated Guideline on Good Clinical Practice and in compliance with Independent Ethics Committees /Institutional Review Boards and informed consent regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 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: 1
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Russian Federation: 11
    Worldwide total number of subjects
    28
    EEA total number of subjects
    17
    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)
    24
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was an open-label, dose-ascending study to assess the PK, pharmacodynamics (PD), safety and tolerability of a single dose of lanreotide PRF. 17 centres recruited adult subjects with acromegaly into 3 lanreotide PRF treatment cohorts (180 milligrams [mg], 270 mg and 360 mg).

    Pre-assignment
    Screening details
    		 Screening of subjects took place 28 to 42 days before administration of study treatment (Day −42 to Day −28). Overall, 60 subjects were screened during this run-in period; 32 of whom were screening failures and 28 subjects were enrolled and treated with lanreotide PRF.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 180 mg Lanreotide PRF
    Arm description
    		 On Day 1, 3 initial subjects in Cohort 1 received a subcutaneous injection of 180 mg lanreotide PRF and a 12-week treatment period then commenced. The dose escalation proceeded with a 3+3+3 scheme. If 0 or 1 out of the 3 dosed subjects had experienced a Dose Limiting Toxicity (DLT), 3 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the Data Review committee (DRC) would have allowed the dose to be escalated to 270 mg (Cohort 2). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until end of study (EOS) at Week 25 or early withdrawal (EW).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide PRF
    Investigational medicinal product code
    Other name
    Lanreotide acetate
    Pharmaceutical forms
    Prolonged-release solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock on Day 1 of the 12 week treatment period. The formulation was supplied in prefilled syringe and delivered 180 mg lanreotide base.

    Arm title
    		 270 mg Lanreotide PRF
    Arm description
    		 On Day 1, 1 initial subject in Cohort 2 received 270 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 2 subjects were treated and reviewed on a 1+2+2+2+2 scheme. If no DLT was experienced, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have stopped, and the dose was declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the DRC would have allowed dose to be escalated to 360 mg (Cohort 3). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide PRF
    Investigational medicinal product code
    Other name
    Lanreotide acetate
    Pharmaceutical forms
    Prolonged-release solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock on Day 1 of the 12 week treatment period. The formulation was supplied in a prefilled syringe and delivered 270 mg lanreotide base.

    Arm title
    		 360 mg Lanreotide PRF
    Arm description
    		 On Day 1, 2 initial subjects in Cohort 3 received 360 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 3 subjects were treated and reviewed on a 2+2+2+3 scheme. An additional subject was also dosed in this cohort as it was considered unethical to exclude an eligible subject. If 0 or 1 subject had experienced a DLT, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose was declared the maximum administered dose. At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide PRF
    Investigational medicinal product code
    Other name
    Lanreotide acetate
    Pharmaceutical forms
    Prolonged-release solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock on Day 1 of the 12 week treatment period. The formulation was supplied in a prefilled syringe and delivered 360 mg lanreotide base.

    Number of subjects in period 1
    		180 mg Lanreotide PRF 270 mg Lanreotide PRF 360 mg Lanreotide PRF
    Started
    9
    9
    10
    Completed
    5
    6
    7
    Not completed
    4
    3
    3
         Consent withdrawn by subject
    -
    -
    1
         Insulin like Growth Factor-1 increased
    3
    2
    2
         Personal Reasons
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    180 mg Lanreotide PRF
    Reporting group description
    		 On Day 1, 3 initial subjects in Cohort 1 received a subcutaneous injection of 180 mg lanreotide PRF and a 12-week treatment period then commenced. The dose escalation proceeded with a 3+3+3 scheme. If 0 or 1 out of the 3 dosed subjects had experienced a Dose Limiting Toxicity (DLT), 3 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the Data Review committee (DRC) would have allowed the dose to be escalated to 270 mg (Cohort 2). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until end of study (EOS) at Week 25 or early withdrawal (EW).

    Reporting group title
    270 mg Lanreotide PRF
    Reporting group description
    		 On Day 1, 1 initial subject in Cohort 2 received 270 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 2 subjects were treated and reviewed on a 1+2+2+2+2 scheme. If no DLT was experienced, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have stopped, and the dose was declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the DRC would have allowed dose to be escalated to 360 mg (Cohort 3). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW.

    Reporting group title
    360 mg Lanreotide PRF
    Reporting group description
    		 On Day 1, 2 initial subjects in Cohort 3 received 360 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 3 subjects were treated and reviewed on a 2+2+2+3 scheme. An additional subject was also dosed in this cohort as it was considered unethical to exclude an eligible subject. If 0 or 1 subject had experienced a DLT, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose was declared the maximum administered dose. At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW.

    Reporting group values
    		 180 mg Lanreotide PRF 270 mg Lanreotide PRF 360 mg Lanreotide PRF Total
    Number of subjects
    		 9 9 10 28
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 8 9 7 24
        From 65-84 years
    		 1 0 3 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.4 ( 7.2 ) 52.1 ( 8.7 ) 56.2 ( 11.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 5 4 15
        Male
    		 3 4 6 13
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 0 0
        White
    		 9 9 10 28
        More than one race
    		 0 0 0 0
        Inknown or Not Reported
    		 0 0 0 0
    Prior Acromegaly Medication
    Units: Subjects
        Octreotide Long Acting Release (LAR)
    		 9 7 7 23
        Lanreotide Autogel
    		 0 2 3 5

    End points

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    End points reporting groups
    Reporting group title
    180 mg Lanreotide PRF
    Reporting group description
    		 On Day 1, 3 initial subjects in Cohort 1 received a subcutaneous injection of 180 mg lanreotide PRF and a 12-week treatment period then commenced. The dose escalation proceeded with a 3+3+3 scheme. If 0 or 1 out of the 3 dosed subjects had experienced a Dose Limiting Toxicity (DLT), 3 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the Data Review committee (DRC) would have allowed the dose to be escalated to 270 mg (Cohort 2). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until end of study (EOS) at Week 25 or early withdrawal (EW).

    Reporting group title
    270 mg Lanreotide PRF
    Reporting group description
    		 On Day 1, 1 initial subject in Cohort 2 received 270 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 2 subjects were treated and reviewed on a 1+2+2+2+2 scheme. If no DLT was experienced, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have stopped, and the dose was declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the DRC would have allowed dose to be escalated to 360 mg (Cohort 3). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW.

    Reporting group title
    360 mg Lanreotide PRF
    Reporting group description
    		 On Day 1, 2 initial subjects in Cohort 3 received 360 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 3 subjects were treated and reviewed on a 2+2+2+3 scheme. An additional subject was also dosed in this cohort as it was considered unethical to exclude an eligible subject. If 0 or 1 subject had experienced a DLT, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose was declared the maximum administered dose. At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW.

    Subject analysis set title
    Lanreotide PK Set: 180 mg Lanreotide PRF
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK valid population consisted of subjects who received at least 1 dose and had no major protocol deviations affecting the PK variables, and who had a sufficient number of serum lanreotide concentrations to estimate the main PK parameters. The lanreotide PK dataset included the 9 subjects from the PK valid population who were not pre-treated with lanreotide and who received 1 deep subcutaneous injection of 180 mg lanreotide PRF.

    Subject analysis set title
    Lanreotide PK Set: 270 mg Lanreotide PRF
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK valid population consisted of subjects who received at least 1 dose and had no major protocol deviations affecting the PK variables, and who had a sufficient number of serum lanreotide concentrations to estimate the main PK parameters. The lanreotide PK dataset included the 7 subjects from the PK valid population who were not pre-treated with lanreotide and who received 1 deep subcutaneous injection of 270 mg lanreotide PRF. The 2 subjects previously treated with a stable dose of lanreotide Autogel were expected to have a detectable pre-dose concentration and it was considered relevant to exclude them.

    Subject analysis set title
    Lanreotide PK Set: 360 mg Lanreotide PRF
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK valid population consisted of subjects who received at least 1 dose and had no major protocol deviations affecting the PK variables, and who had a sufficient number of serum lanreotide concentrations to estimate the main PK parameters. The lanreotide PK dataset included 6 subjects from the PK valid population who were not pre-treated with lanreotide and who received 1 deep subcutaneous injection of 360 mg lanreotide PRF. The 3 subjects previously treated with a stable dose of lanreotide Autogel were expected to have a detectable pre-dose concentration and it was considered relevant to exclude them.

    Subject analysis set title
    Glycofurol PK Set: 180 mg Lanreotide PRF
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK valid population consisted of subjects who received at least 1 dose and had no major protocol deviations affecting the PK variables, and who had a sufficient number of serum lanreotide concentrations to estimate the main PK parameters. This glycofurol dataset included 9 subjects from the PK valid population who had a sufficient number of serum glycofurol concentrations to estimate the main glycofurol PK parameters and who received 1 deep subcutaneous injection of 180 mg lanreotide PRF.

    Subject analysis set title
    Glycofurol PK Set: 270 mg Lanreotide PRF
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK valid population consisted of subjects who received at least 1 dose and had no major protocol deviations affecting the PK variables, and who had a sufficient number of serum lanreotide concentrations to estimate the main PK parameters. This glycofurol dataset included 9 subjects from the PK valid population who had a sufficient number of serum glycofurol concentrations to estimate the main glycofurol PK parameters and who received 1 deep subcutaneous injection of 270 mg lanreotide PRF.

    Primary: Determination of the MTD by Number of Subjects With DLTs.

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    End point title
    		 Determination of the MTD by Number of Subjects With DLTs. [1]
    End point description
    The MTD was defined based on the DLTs observed in each cohort. A DLT was defined as an adverse event (AE) (excluding anorexia and fatigue) or an abnormal laboratory value occurring within the first week (up to Week 2) following lanreotide PRF administration and during the entire study duration, assessed as unrelated to acromegaly, intercurrent illness or concomitant medications and which met any of the pre-established toxicity criteria. If no DLTs were reported then no MTD could be defined. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment.
    End point type
    Primary
    End point timeframe
    From Day 1 up to Week 25.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As this was a dose ascending study, no comparative analyses were performed.
    End point values
    		 180 mg Lanreotide PRF 270 mg Lanreotide PRF 360 mg Lanreotide PRF
    Number of subjects analysed
    9
    9
    10
    Units: Subjects
    0
    0
    0
    No statistical analyses for this end point

    Primary: PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax).

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    End point title
    		 PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax). [2]
    End point description
    Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide Cmax values were determined using non-compartmental analysis. Only subjects with data available for analysis and who were not pre-treated with lanreotide are presented.
    End point type
    Primary
    End point timeframe
    From Baseline (pre-dose) up to Day 85
    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: As this was a dose ascending study, no comparative analyses were performed.
    End point values
    		 Lanreotide PK Set: 180 mg Lanreotide PRF Lanreotide PK Set: 270 mg Lanreotide PRF Lanreotide PK Set: 360 mg Lanreotide PRF
    Number of subjects analysed
    9
    7
    6
    Units: nanograms/millilitre (ng/mL)
        arithmetic mean (standard deviation)
    19.0 ( 15.7 )
    14.0 ( 10.3 )
    20.5 ( 5.86 )
    No statistical analyses for this end point

    Primary: PK Analysis of Lanreotide: Time to Reach Maximum Serum Concentration (Tmax).

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    End point title
    		 PK Analysis of Lanreotide: Time to Reach Maximum Serum Concentration (Tmax). [3]
    End point description
    Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Median serum lanreotide Tmax values were determined using non-compartmental analysis. Only subjects with data available for analysis and who were not pre-treated with lanreotide are presented.
    End point type
    Primary
    End point timeframe
    From Baseline (pre-dose) up to Week 25.
    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: As this was a dose ascending study, no comparative analyses were performed.
    End point values
    		 Lanreotide PK Set: 180 mg Lanreotide PRF Lanreotide PK Set: 270 mg Lanreotide PRF Lanreotide PK Set: 360 mg Lanreotide PRF
    Number of subjects analysed
    9
    7
    6
    Units: days
        median (full range (min-max))
    0.250 (0.167 to 1.00)
    0.253 (0.167 to 1.00)
    0.250 (0.167 to 0.333)
    No statistical analyses for this end point

    Primary: PK Analysis of Lanreotide: Apparent Terminal Elimination Half-life (t1/2).

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    End point title
    		 PK Analysis of Lanreotide: Apparent Terminal Elimination Half-life (t1/2). [4]
    End point description
    Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide t1/2 values were determined using non-compartmental analysis. Only values fulfilling the determination rules for t1/2 were analysed. Only subjects with data available for analysis and who were not pre-treated with lanreotide are presented.
    End point type
    Primary
    End point timeframe
    From Baseline (pre-dose) up to Week 25.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As this was a dose ascending study, no comparative analyses were performed.
    End point values
    		 Lanreotide PK Set: 180 mg Lanreotide PRF Lanreotide PK Set: 270 mg Lanreotide PRF Lanreotide PK Set: 360 mg Lanreotide PRF
    Number of subjects analysed
    7
    5
    4
    Units: days
        arithmetic mean (standard deviation)
    54.2 ( 17.0 )
    61.7 ( 13.9 )
    63.1 ( 13.3 )
    No statistical analyses for this end point

    Primary: PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve From Time 0 to 85 Days (AUC0-85).

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    End point title
    		 PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve From Time 0 to 85 Days (AUC0-85). [5]
    End point description
    Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide AUC0-85 values were determined using non-compartmental analysis. Only subjects with data available for analysis and who were not pre-treated with lanreotide are presented.
    End point type
    Primary
    End point timeframe
    From Baseline (pre-dose) up to Week 25.
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As this was a dose ascending study, no comparative analyses were performed.
    End point values
    		 Lanreotide PK Set: 180 mg Lanreotide PRF Lanreotide PK Set: 270 mg Lanreotide PRF Lanreotide PK Set: 360 mg Lanreotide PRF
    Number of subjects analysed
    9
    7
    6
    Units: ng*day/mL
        arithmetic mean (standard deviation)
    161 ( 97.6 )
    179 ( 54.2 )
    265 ( 87.1 )
    No statistical analyses for this end point

    Primary: PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUC0-∞).

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    End point title
    		 PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUC0-∞). [6]
    End point description
    Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide AUC0-∞ values were determined using non-compartmental analysis. Only values fulfilling the accuracy determination rules for AUC0-∞ were analysed. Only subjects with data available for analysis and who were not pre-treated with lanreotide are presented. 9999999 = not determined (i.e. when more than 1/3 of the values did not fulfil accuracy determination rules, the descriptive statistics were not calculated).
    End point type
    Primary
    End point timeframe
    From Baseline (pre-dose) up to Week 25.
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As this was a dose ascending study, no comparative analyses were performed.
    End point values
    		 Lanreotide PK Set: 180 mg Lanreotide PRF Lanreotide PK Set: 270 mg Lanreotide PRF Lanreotide PK Set: 360 mg Lanreotide PRF
    Number of subjects analysed
    3
    2
    3
    Units: ng*day/mL
        arithmetic mean (standard deviation)
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    No statistical analyses for this end point

    Secondary: Overall Summary of Number of Subjects With AEs.

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    End point title
    		 Overall Summary of Number of Subjects With AEs.
    End point description
    AEs reported by the investigators using the National Cancer Institute–Common Toxicity Criteria (NCI CTCAE) classification (Version 4.03) and incidence of all reported treatment emergent AEs (TEAEs) and serious AEs (SAEs) are presented by dose cohort for the safety population. AEs were assigned to a NCI CTCAE Grade from 1 through 5 as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. TEAEs were defined as any AE that occurs during the active phase of the study (between the start of the 3 month treatment period and 3 months after the end of study treatment). The worst intensity of TEAES at each grade are reported for all and for related TEAES. In the event of multiple occurrences of the same AEs being reported by the same subject, the maximum intensity and the most serious causality were reported.
    End point type
    Secondary
    End point timeframe
    From Day -42 up to Week 25.
    End point values
    		 180 mg Lanreotide PRF 270 mg Lanreotide PRF 360 mg Lanreotide PRF
    Number of subjects analysed
    9
    9
    10
    Units: Subjects
        TEAEs
    6
    7
    7
        Related TEAEs
    2
    3
    4
        TEAEs leading to study drug withdrawal
    0
    0
    0
        SAEs
    1
    0
    1
        Serious TEAEs
    1
    0
    1
        Serious related TEAEs
    0
    0
    0
        AEs leading to death
    0
    0
    0
        Worst TEAE: Grade 1
    1
    3
    5
        Worst TEAE: Grade 2
    3
    4
    1
        Worst TEAE: Grade 3
    2
    0
    1
        Worst TEAE: Grade 4
    0
    0
    0
        Worst TEAE: Grade 5
    0
    0
    0
        Worst related TEAE: Grade 1
    0
    1
    3
        Worst related TEAE: Grade 2
    2
    2
    1
        Worst related TEAE: Grade 3
    0
    0
    0
        Worst related TEAE: Grade 4
    0
    0
    0
        Worst related TEAE: Grade 5
    0
    0
    0
    No statistical analyses for this end point

    Secondary: PK Analysis of Glycofurol Excipients: Cmax.

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    End point title
    		 PK Analysis of Glycofurol Excipients: Cmax.
    End point description
    Blood samples for determination of the excipients (N1-glycofurol and N2-glycofurol) serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8, 12 and 24 hours post-dose and on Days 3 and 5. Mean serum N1- glycofurol and N2-glycofurol Cmax values were determined using non-compartmental analysis. Only subjects with data available for analysis are presented. Due to bioanalytical issues, no results for the excipient N1-glycofurol and N2-glycofurol for 360 mg Lanreotide PRF (cohort 3) were available at the time of the PK analysis.
    End point type
    Secondary
    End point timeframe
    From Baseline (pre-dose) up to Day 5.
    End point values
    		 Glycofurol PK Set: 180 mg Lanreotide PRF Glycofurol PK Set: 270 mg Lanreotide PRF
    Number of subjects analysed
    9
    9
    Units: ng/mL
    arithmetic mean (standard deviation)
        N1-glycofurol
    75.4 ( 65.6 )
    61.7 ( 17.2 )
        N2-glycofurol
    79.7 ( 72.1 )
    62.1 ( 18.4 )
    No statistical analyses for this end point

    Secondary: PK Analysis of Glycofurol Excipients: Tmax.

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    End point title
    		 PK Analysis of Glycofurol Excipients: Tmax.
    End point description
    Blood samples for determination of the excipients (N1-glycofurol and N2-glycofurol) serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8, 12 and 24 hours post-dose and on Days 3 and 5. Median serum N1-glycofurol and N2-glycofurol Tmax values were determined using non-compartmental analysis. Only subjects with data available for analysis are presented. Due to bioanalytical issues, no results for the excipient N1-glycofurol and N2-glycofurol for 360 mg Lanreotide PRF (cohort 3) were available at the time of the PK analysis.
    End point type
    Secondary
    End point timeframe
    From Baseline (pre-dose) up to Day 5.
    End point values
    		 Glycofurol PK Set: 180 mg Lanreotide PRF Glycofurol PK Set: 270 mg Lanreotide PRF
    Number of subjects analysed
    9
    9
    Units: hours
    median (full range (min-max))
        N1-glycofurol
    2.00 (1.00 to 3.92)
    2.00 (1.00 to 4.00)
        N2-glycofurol
    2.00 (1.00 to 3.92)
    2.00 (1.00 to 4.00)
    No statistical analyses for this end point

    Secondary: PK Analysis of Glycofurol Excipients: AUC0-∞ and Area Under the Serum Concentration Time Curve From Time 0 to Last Quantifiable Timepoint (AUC0-t).

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    End point title
    		 PK Analysis of Glycofurol Excipients: AUC0-∞ and Area Under the Serum Concentration Time Curve From Time 0 to Last Quantifiable Timepoint (AUC0-t).
    End point description
    Blood samples for determination of the excipients (N1-glycofurol and N2-glycofurol) serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8, 12 and 24 hours post-dose and on Days 3 and 5. Mean serum N1-glycofurol and N2-glycofurol AUC0-∞ and AUC0-t values were determined using non-compartmental analysis. Only AUC0-∞ values fulfilling the accuracy determination rules were analysed. Due to bioanalytical issues, no results for the excipient N1-glycofurol and N2-glycofurol for 360 mg Lanreotide PRF (cohort 3) were available at the time of the PK analysis.
    End point type
    Secondary
    End point timeframe
    From Baseline (pre-dose) up to Day 5.
    End point values
    		 Glycofurol PK Set: 180 mg Lanreotide PRF Glycofurol PK Set: 270 mg Lanreotide PRF
    Number of subjects analysed
    9 [7]
    9 [8]
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        AUC0-∞: N1-glycofurol
    779 ( 205 )
    1049 ( 195 )
        AUC0-∞: N2-glycofurol
    1008 ( 268 )
    1359 ( 282 )
        AUC0-t: N1-glycofurol
    783 ( 193 )
    1082 ( 238 )
        AUC0-t: N2-glycofurol
    1007 ( 257 )
    1360 ( 285 )
    Notes
    [7] - AUC0-∞: 8 subjects analysed.
    [8] - AUC0-∞: 8 subjects analysed.
    No statistical analyses for this end point

    Secondary: PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1).

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    End point title
    		 PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1).
    End point description
    Blood samples were collected for the determination of IGF-1 in serum at Baseline (pre-dose), 6 hours post-dose and at Weeks 5, 9 and 13. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Serum concentrations of IGF-1 were calculated using the Immulite 2000 Platform for all subjects in the safety population. The production of the reagent kits was stopped by the vendor during the study. The old reagent kits were used for Cohorts 1 and 2 until their expiry date and then the kits were switched to a new reagent and used for remaining subjects in Cohorts 2 and 3. Summary data for serum concentrations of IGF-1 were obtained using both methods (old and new reagent) and the mean change from Baseline at each time point is presented. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment. Only subjects with data available for analysis are presented. 9999999 = not calculable.
    End point type
    Secondary
    End point timeframe
    From Baseline (pre-dose) up to Week 25.
    End point values
    		 180 mg Lanreotide PRF 270 mg Lanreotide PRF 360 mg Lanreotide PRF
    Number of subjects analysed
    9 [9]
    9 [10]
    10 [11]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Old Reagent: 6 hours post-dose
    -1.8 ( 18.9 )
    -7.1 ( 17.2 )
    -46.5 ( 46.7 )
        Old Reagent: Week 5
    2.4 ( 41.3 )
    27.9 ( 32.8 )
    -32.0 ( 49.5 )
        Old Reagent: Week 9
    72.3 ( 61.3 )
    71.4 ( 72.7 )
    9999999 ( 9999999 )
        Old Reagent: Week 13
    53.4 ( 67.9 )
    111.1 ( 129.3 )
    9999999 ( 9999999 )
        Old Reagent: Week 17
    48.3 ( 62.7 )
    96.2 ( 43.8 )
    9999999 ( 9999999 )
        Old Reagent: Week 21
    72.4 ( 84.4 )
    135.5 ( 80.5 )
    9999999 ( 9999999 )
        Old Reagent: Week 25 (EOS/EW)
    86.3 ( 81.4 )
    136.4 ( 83.5 )
    9999999 ( 9999999 )
        New Reagent: 6 hours post-dose
    9999999 ( 9999999 )
    6.0 ( 5.7 )
    -11.6 ( 15.9 )
        New Reagent: Week 5
    9999999 ( 9999999 )
    3.0 ( 8.5 )
    1.3 ( 38.4 )
        New Reagent: Week 9
    9999999 ( 9999999 )
    13.0 ( 9.9 )
    25.2 ( 33.6 )
        New Reagent: Week 13
    9999999 ( 9999999 )
    30.0 ( 43.8 )
    47.1 ( 43.9 )
        New Reagent: Week 17
    9999999 ( 9999999 )
    20.5 ( 17.7 )
    40.9 ( 46.8 )
        New Reagent: Week 21
    9999999 ( 9999999 )
    65.0 ( 58.0 )
    56.9 ( 35.6 )
        New Reagent: Week 25 (EOS/EW)
    9999999 ( 9999999 )
    45.5 ( 17.7 )
    64.1 ( 68.0 )
    Notes
    [9] - Old : Weeks 13, 17 (n=7), 21 (n=5) New: all weeks (n=0)
    [10] - Old Reagent: 6 h (n=8) Weeks 17 (n=6), 21 (n=4) New Reagent: all weeks (n= 2)
    [11] - Old: 6 h (n=4) Weeks 5 (n=2), 9-25 (n=0) New: 6 h & Weeks 9 (n=9), 17 (n=8), 21 (n=7)
    No statistical analyses for this end point

    Secondary: PD Analysis: Mean Change From Baseline in Growth Hormone (GH).

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    End point title
    		 PD Analysis: Mean Change From Baseline in Growth Hormone (GH).
    End point description
    GH cycle assessments were performed by taking 5 samples in the morning (with a sample taken every 30 minutes for 2 hours) at Baseline (pre-dose), Week 5 and Week 13. Summary data for the mean of the 5 samplings of the GH cycle were generated and the mean change from Baseline at each time point is presented. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment. Only subjects with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    From Baseline (pre-dose) up to Week 13.
    End point values
    		 180 mg Lanreotide PRF 270 mg Lanreotide PRF 360 mg Lanreotide PRF
    Number of subjects analysed
    9 [12]
    9
    10
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 5
    0.268 ( 0.344 )
    0.367 ( 0.926 )
    -0.228 ( 0.777 )
        Week 13
    0.667 ( 0.473 )
    0.684 ( 0.863 )
    0.003 ( 1.761 )
    Notes
    [12] - Week 13 (n=7)
    No statistical analyses for this end point

    Secondary: PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4).

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    End point title
    		 PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4).
    End point description
    Blood samples were collected for the determination of FT3 and FT4 in serum at Baseline (pre-dose) and at Weeks 2, 5, 13 and 25 (or EW). Summary data for serum concentrations of FT3 and FT4 were calculated and the mean change from Baseline at each time point is presented. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment. Only subjects with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    From Baseline (pre-dose) up to Week 25.
    End point values
    		 180 mg Lanreotide PRF 270 mg Lanreotide PRF 360 mg Lanreotide PRF
    Number of subjects analysed
    9 [13]
    9 [14]
    10 [15]
    Units: picomole/litre (L)
    arithmetic mean (standard deviation)
        FT3: Week 2
    -0.278 ( 0.518 )
    -0.164 ( 0.517 )
    -0.374 ( 0.479 )
        FT3: Week 5
    -0.132 ( 0.429 )
    0.170 ( 0.705 )
    0.170 ( 0.452 )
        FT3: Week 13
    0.100 ( 0.590 )
    0.191 ( 0.912 )
    0.438 ( 0.481 )
        FT3: Week 25 (EOS/EW)
    0.268 ( 0.388 )
    0.295 ( 0.626 )
    0.396 ( 0.684 )
        FT4: Week 2
    0.50 ( 1.58 )
    -0.02 ( 1.43 )
    -0.68 ( 1.07 )
        FT4: Week 5
    1.18 ( 2.31 )
    0.33 ( 2.52 )
    -0.67 ( 2.19 )
        FT4: Week 13
    1.69 ( 2.16 )
    1.80 ( 3.59 )
    -0.46 ( 1.39 )
        FT4: Week 25 (EOS/EW)
    0.81 ( 2.5 )
    1.06 ( 2.39 )
    0.38 ( 2.03 )
    Notes
    [13] - Week 13 (n=7)
    [14] - FT4: Week 25 (n=8)
    [15] - Weeks 2&5 (n=9)
    No statistical analyses for this end point

    Secondary: PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH).

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    End point title
    		 PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH).
    End point description
    Blood samples were collected for the determination of TSH in serum at Baseline (pre-dose) and at Weeks 2, 5, 13 and 25 (or EW). Summary data for serum concentrations of TSH were calculated and the mean change from Baseline at each time point is presented. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment. Only subjects with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    From Baseline (pre-dose) up to Week 25.
    End point values
    		 180 mg Lanreotide PRF 270 mg Lanreotide PRF 360 mg Lanreotide PRF
    Number of subjects analysed
    9 [16]
    9 [17]
    10 [18]
    Units: mIU/L
    arithmetic mean (standard deviation)
        Week 2
    -0.222 ( 0.562 )
    0.119 ( 0.315 )
    0.047 ( 0.844 )
        Week 5
    -0.156 ( 0.577 )
    0.062 ( 0.670 )
    0.051 ( 0.534 )
        Week 13
    -0.404 ( 0.710 )
    -0.060 ( 0.897 )
    0.601 ( 1.080 )
        Week 25 (EOS/EW)
    -0.480 ( 0.593 )
    0.073 ( 0.450 )
    0.235 ( 0.671 )
    Notes
    [16] - Week 13 (n=7)
    [17] - Week 25 (n=8)
    [18] - Weeks 2&5 (n=9)
    No statistical analyses for this end point

    Secondary: PD Analysis: Mean Change From Baseline in Prolactin.

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    End point title
    		 PD Analysis: Mean Change From Baseline in Prolactin.
    End point description
    Blood samples were collected for the determination of prolactin in serum at Baseline (pre-dose) and at Weeks 2, 5, 13 and 25 (or EW). Summary data for serum concentration of prolactin were calculated and the mean change from Baseline at each time point is presented. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment. Only subjects with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    From Baseline (pre-dose) up to Week 25.
    End point values
    		 180 mg Lanreotide PRF 270 mg Lanreotide PRF 360 mg Lanreotide PRF
    Number of subjects analysed
    9 [19]
    9 [20]
    10 [21]
    Units: mU/L
    arithmetic mean (standard deviation)
        Week 2
    -33.2 ( 54.9 )
    37.6 ( 36.1 )
    1.0 ( 49.3 )
        Week 5
    -10.4 ( 53.2 )
    16.3 ( 81.2 )
    0.3 ( 50.7 )
        Week 13
    -1.9 ( 66.5 )
    33.9 ( 78.5 )
    -6.4 ( 47.1 )
        Week 25 (EOS/EW)
    19.3 ( 53.5 )
    58.3 ( 86.6 )
    -3.1 ( 55.9 )
    Notes
    [19] - Week 13 (n=7)
    [20] - Week 25 (n=8)
    [21] - Week 2&5 (n=9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Each subject was assessed for TEAEs over an approximate 6 month period. TEAEs were collected over the 32 month study duration.
    Adverse event reporting additional description
    TEAES were monitored for the safety population which was defined as all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    180 mg Lanreotide PRF
    Reporting group description
    		 On Day 1, 3 initial subjects in Cohort 1 received 180 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. The dose escalation proceeded with a 3+3+3 scheme. If 0 or 1 out of the 3 dosed subjects had experienced a DLT, 3 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have stopped, and the dose declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the DRC would have allowed the dose to be escalated to 270 mg (Cohort 2). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW.

    Reporting group title
    270 mg Lanreotide PRF
    Reporting group description
    		 On Day 1, 1 initial subject in Cohort 2 received 270 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 2 subjects were treated and reviewed on a 1+2+2+2+2 scheme. If no DLT was experienced, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have stopped, and the dose was declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the DRC would have allowed dose to be escalated to 360 mg (Cohort 3). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW.

    Reporting group title
    360 mg Lanreotide PRF
    Reporting group description
    		 On Day 1, 2 initial subjects in Cohort 3 received 360 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 3 subjects were treated and reviewed on a 2+2+2+3 scheme. An additional subject was also dosed in this cohort as it was considered unethical to exclude an eligible subject. If 0 or 1 subject had experienced a DLT, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose was declared the maximum administered dose. At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW.

    Serious adverse events
    		 180 mg Lanreotide PRF 270 mg Lanreotide PRF 360 mg Lanreotide PRF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 180 mg Lanreotide PRF 270 mg Lanreotide PRF 360 mg Lanreotide PRF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 9 (66.67%)
    7 / 9 (77.78%)
    7 / 10 (70.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Orthostatic Hypotension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Vasculitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    2
    Influenza Like Illness
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Injection Site Haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Injection Site Induration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Injection Site Pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Injection Site Swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Breast Pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Postmenopausal Haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    4
    0
    Cardiac disorders
    Sinus Bradycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    3
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    2 / 10 (20.00%)
         occurrences all number
    0
    1
    3
    Paraesthesia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Iron Deficiency Anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Lymphopenia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Conjunctival Hyperaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Vision Blurred
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 9 (33.33%)
    0 / 10 (0.00%)
         occurrences all number
    2
    3
    0
    Faeces Soft
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Inguinal Hernia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    3
    Renal and urinary disorders
    Renal Cyst
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Flank Pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Pain In Extremity
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory Tract Infection Viral
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2014
    To provide clarification on questions received from the authorities associated with safety monitoring, the PK of lanreotide PRF, the dose escalation criteria and the dose selection rationale.
    12 Jun 2015
    To extend the planned study period to January 2017. To include the option for home visits on Weeks 4, 7, 11, 15, 19 and 23. To increase the IGF-1 limit from within the normal range to <1.3 x upper limit of normal (ULN) and clarify that the assessment during the Screening period must be analysed by the central laboratory. To reduce the period in which the subject had had radiotherapy from 3 years to 2 years prior to study entry. To clarify that any significant renal abnormalities and/or creatinine values ≥1.5 x ULN should be measured during the Screening period and must be analysed by the central laboratory. To include an opportunity to re-test the screening IGF-1 value once if it was just above the 1.3 x ULN limit. To include an option for the Sponsor to conduct an interim analysis in relation to the clinical development of lanreotide PRF.
    27 Jul 2015
    To allow up to 3 subjects previously controlled on lanreotide Autogel to be enrolled per cohort of 9. To amend the title of the protocol to reflect this change to the subjects enrolled from just octreotide LAR to either octreotide LAR or lanreotide Autogel. To allow the screening for subject enrolment regarding IGF-1 levels to be assessed on an IGF-1 level analysed at a local laboratory instead of only at the central laboratory. To update the number of IGF-1 samples and total blood volumes to account for the additional sample collected during screening for assessment by local laboratory. To add an additional subgroup analysis due to the change in subjects eligible for the study - from only octreotide LAR to either octreotide LAR or lanreotide Autogel. To add the possibility not to perform Day 5, according to PK excipient data further to DRC review. If the t1/2 of the excipient was short there was no need to follow it any longer. Also, the excipient PK may have also been removed on Day 3. To add a ±2 day window for Day 1 and 2.
    22 Mar 2016
    To allow the addition of safety information gathered from the phase I study D-FR-52030-345 conducted with lanreotide PRF for transparency reasons. To increase the frequency of DRC meetings to ensure closer subject safety monitoring. To extend the study timelines and increase the number of participating sites. To allow more flexibility for the run-in period by extending the run-in period up to 6 weeks under specified circumstances.
    16 Dec 2016
    To allow inclusion of subjects with asymptomatic gallstones or sludge, and the re-screening of subjects who previously failed this exclusion criteria. To change the DRC frequency for Cohort 3 from 2+2+2+2+1 to 2+2+2+3. To better clarify the follow-up and reporting of AEs. To include details of withdrawal of consent for biobanking in the protocol for clarity and amend the procedure for the shipment of biobanking samples.

    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.
    No glycofurol excipient PK results are available for 360mg Lanreotide PRF at this time. A total of 28 subjects were allowed to enrol rather than the 27 subjects planned as it was considered unethical not to enrol a consented eligible subject.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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