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    Clinical Trial Results:
    Open label extension study of lanreotide Autogel 120 mg in patients with non functioning entero-pancreatic endocrine tumour

    Summary
    EudraCT number
    		 2008-004019-36
    Trial protocol
    		 FR   CZ   SK   BE   ES   PL   GB   SE   IT  
    Global end of trial date
    04 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Dec 2017
    First version publication date
    28 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2-55-52030-729
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00842348
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ipsen Pharma SAS
    Sponsor organisation address
    65 quai Georges Gorse, Boulogne Billancourt, Cedex, France, 92650
    Public contact
    Medical Director, Oncology, Ipsen Pharma SAS, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Oncology, Ipsen Pharma SAS, 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
    04 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Study 2-55-52030-729 (hereafter referred to as extension Study 729) assessed the long term safety of administration of lanreotide Autogel 120 milligrams (mg) every 28 days in patients with non functioning entero-pancreatic neuroendocrine tumour (NET). Study 729 is the extension to the original study protocol, 2-55-52030-726 (hereafter referred to as core Study 726) which was a randomised, double-blind, placebo-controlled, parallel group study in patients with metastatic or locally advanced non functioning entero-pancreatic NET. Eligible patients from core Study 726 could be enrolled in the open label extension Study 729 but enrolment was not mandatory. In extension Study 729, all patients received the same treatment (lanreotide Autogel 120 mg) but certain results analyses were performed using patients as randomised in the core Study 726. As such, overall enrolment for the trial (enrolled per country and per age group) is presented for the core Study 726.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki, and in accordance with the International Conference on Harmonisation Consolidated Guideline on Good Clinical Practice. This study also adhered to all local regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Feb 2009
    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
    Belgium: 4
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    France: 41
    Country: Number of subjects enrolled
    India: 4
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    United States: 30
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Germany: 14
    Worldwide total number of subjects
    204
    EEA total number of subjects
    170
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    111
    From 65 to 84 years
    91
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 In core Study 726, patients were enrolled at 48 sites across 14 countries (204 randomised to receive study treatment). In extension Study 729, patients were enrolled at 24 sites across 10 countries (89 enrolled to receive open label study treatment). The study was initiated in February 2009 and completed in December 2015

    Pre-assignment
    Screening details
    		 Patients treated in core Study 726 were eligible for entry into this extension study if they met either of the following criteria: 1. Stable disease after 96 weeks of treatment, irrespective of treatment received during Study 726, or 2. Disease progression (PD) during course of Study 726 and the code break showed the patient had received placebo.

    Period 1
    Period 1 title
    Start core Study 726 to start Study 729
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    In core Study 726, 2 sets of individual sealed code break envelopes were prepared by an Ipsen Randomisation Manager to enable code break procedures of individual subjects without compromising the blind of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LA:LA (Study 726:Study 729)
    Arm description
    		 Patients who received lanreotide Autogel 120 mg in core Study 726 and who continued to receive open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as LA:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide Autogel
    Investigational medicinal product code
    Lanreotide Autogel 120 mg
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lanreotide Autogel 120 mg was administered every 28 days via deep subcutaneous (s.c.) injections (in the superior external quadrant of the buttock).

    Arm title
    		 PB:LA (Study 726:Study 729)
    Arm description
    		 Patients who received placebo in core Study 726 and who received open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as PB:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Saline solution 0.9% administered via deep s.c. injection every 28 days.

    Number of subjects in period 1
    		LA:LA (Study 726:Study 729) PB:LA (Study 726:Study 729)
    Started
    101
    103
    Completed
    42
    47
    Not completed
    59
    56
         Did not enter Study 729
    59
    56
    Period 2
    Period 2 title
    Study 729
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LA:LA (Study 726:Study 729)
    Arm description
    		 Patients who received lanreotide Autogel 120 mg in core Study 726 and who continued to receive open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as LA:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide Autogel
    Investigational medicinal product code
    Lanreotide Autogel 120 mg
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lanreotide Autogel 120 mg was administered every 28 days via deep subcutaneous (s.c.) injections (in the superior external quadrant of the buttock).

    Arm title
    		 PB:LA (Study 726:Study 729)
    Arm description
    		 Patients who received placebo in core Study 726 and who received open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as PB:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanreotide Autogel
    Investigational medicinal product code
    Lanreotide Autogel 120 mg
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lanreotide Autogel 120 mg was administered every 28 days via deep subcutaneous (s.c.) injections (in the superior external quadrant of the buttock).

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Since certain efficacy data is reported for the intention-to-treat (ITT) population which comprised all patients randomised in core Study 726, it was necessary for Subject Disposition to represent those enrolled in this preceding study. Thus, Period 1 presents data for patients enrolled in core Study 726 until the start of extension Study 729, and Period 2 presents data for patients enrolled in extension Study 729. Period 2 is therefore the baseline period for this extension study.
    Number of subjects in period 2 [2]
    		LA:LA (Study 726:Study 729) PB:LA (Study 726:Study 729)
    Started
    42
    47
    Completed
    16
    9
    Not completed
    26
    38
         Adverse event, serious fatal
    1
    2
         Sponsor's decision
    1
    -
         Consent withdrawn by subject
    2
    4
         Due to non-availability of investigational product
    -
    1
         Adverse event, non-fatal
    1
    1
         Due to Sponsor stopping the study
    1
    1
         PD (including deaths due to PD)
    18
    28
         Surgical resection
    1
    -
         Protocol deviation
    1
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number enrolled worldwide corresponds to all patients randomised in core Study 726 (n=204). This was necessary due to the presentation of certain efficacy data for this patient population (i.e. ITT population). Baseline characteristics are presented for the safety population which comprised all patients who received at least one dose of lanreotide Autogel in extension Study 729 (n=89).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LA:LA (Study 726:Study 729)
    Reporting group description
    		 Patients who received lanreotide Autogel 120 mg in core Study 726 and who continued to receive open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as LA:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.

    Reporting group title
    PB:LA (Study 726:Study 729)
    Reporting group description
    		 Patients who received placebo in core Study 726 and who received open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as PB:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.

    Reporting group values
    		 LA:LA (Study 726:Study 729) PB:LA (Study 726:Study 729) Total
    Number of subjects
    		 42 47 89
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.8 ± 10.8 61.3 ± 10.2 -
    Gender categorical
    Units: Subjects
        Female
    		 23 22 45
        Male
    		 19 25 44
    Race
    Units: Subjects
        Asian
    		 0 3 3
        Black or African American
    		 1 0 1
        Caucasian/White
    		 41 44 85

    End points

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    End points reporting groups
    Reporting group title
    LA:LA (Study 726:Study 729)
    Reporting group description
    		 Patients who received lanreotide Autogel 120 mg in core Study 726 and who continued to receive open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as LA:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.

    Reporting group title
    PB:LA (Study 726:Study 729)
    Reporting group description
    		 Patients who received placebo in core Study 726 and who received open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as PB:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.
    Reporting group title
    LA:LA (Study 726:Study 729)
    Reporting group description
    		 Patients who received lanreotide Autogel 120 mg in core Study 726 and who continued to receive open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as LA:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.

    Reporting group title
    PB:LA (Study 726:Study 729)
    Reporting group description
    		 Patients who received placebo in core Study 726 and who received open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as PB:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.

    Subject analysis set title
    Total LA (Study 729)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients treated with open label lanreotide Autogel 120 mg (LA) in extension Study 729.

    Subject analysis set title
    Lanreotide Autogel - Randomised Treatment in Study 726
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomised to lanreotide Autogel 120 mg in core Study 726. Patients continuing into extension Study 729 received open label lanreotide Autogel 120 mg once every 28 days.

    Subject analysis set title
    Placebo - Randomised Treatment in Study 726
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomised to placebo in core Study 726. Patients continuing into extension Study 729 received open label lanreotide Autogel 120 mg once every 28 days.

    Primary: Number of Patients with Treatment Emergent Adverse Events (TEAEs) during extension Study 729

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    End point title
    		 Number of Patients with Treatment Emergent Adverse Events (TEAEs) during extension Study 729 [1]
    End point description
    Adverse events (AEs) that were ongoing from core Study 726 at the time of entry into extension Study 729 were transcribed into the case report form (CRF) for Study 729 with a start date corresponding to the original report of this AE in Study 726. All new AEs that started after the last visit in core Study 726 (i.e. irrespective of whether the AE had onset before or after giving informed consent for extension Study 729) were recorded in the CRF for Study 729. An AE was considered as a treatment emergent adverse event (TEAE) for Study 729 if: • It was not present prior to receiving the first dose of study treatment in Study 729; or, • It was present prior to receiving the first dose of study treatment in Study 729 but the intensity increased after the first dose of study treatment in Study 729. Analysis was performed on the the safety population which comprised all patients who received at least one dose of open label lanreotide Autogel in extension Study 729.
    End point type
    Primary
    End point timeframe
    Throughout the study until the completion/early discontinuation visit.
    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: Only descriptive analysis was planned and performed for the primary end point.
    End point values
    		 LA:LA (Study 726:Study 729) PB:LA (Study 726:Study 729) Total LA (Study 729)
    Number of subjects analysed
    42
    47
    89
    Units: Participants
    40
    46
    86
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS): Kaplan-Meier Estimate

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    End point title
    		 Progression Free Survival (PFS): Kaplan-Meier Estimate
    End point description
    The time from randomisation in core Study 726 to the first occurrence of either PD (measured using Response Evaluation Criteria In Solid Tumours criteria) or death in Study 726 or in extension Study 729, or equivalently, the PFS time. Tumour assessments for the placebo group after switching to open label lanreotide Autogel in extension Study 729 were excluded for the purpose of this analysis. Estimation of the median was based on the Kaplan-Meier method. Analysis was performed on the ITT population which comprised all patients randomised in core Study 726 (regardless of whether they continued into extension Study 729). The ITT population was analysed using patients as randomised in core Study 726 (i.e. to either lanreotide Autogel or placebo).
    End point type
    Secondary
    End point timeframe
    Throughout the study (every 24 weeks and at completion/withdrawal visit)
    End point values
    		 Lanreotide Autogel - Randomised Treatment in Study 726 Placebo - Randomised Treatment in Study 726
    Number of subjects analysed
    101
    103
    Units: weeks
        median (confidence interval 95%)
    154.14 (123.57 to 237.43)
    72.00 (48.43 to 84.57)
    No statistical analyses for this end point

    Secondary: Time to Subsequent Disease Progression or Death

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    End point title
    		 Time to Subsequent Disease Progression or Death
    End point description
    The time to subsequent PD or death, defined as time from PD in core Study 726 (while receiving placebo treatment) to subsequent PD or death, in extension Study 729 (while receiving open label lanreotide Autogel treatment). Analysis was performed on the ITT population for the subgroup of patients with PD during placebo treatment in core Study 726 who continued into extension Study 729 (n=32).
    End point type
    Secondary
    End point timeframe
    Throughout the study (every 24 weeks and at completion/withdrawal visit)
    End point values
    		 Placebo - Randomised Treatment in Study 726
    Number of subjects analysed
    32
    Units: weeks
        median (confidence interval 95%)
    76.14 (40.29 to 106.86)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were monitored from the time that the patient withdrew or completed core Study 726 until withdrawal in extension Study 729 (up to maximum duration of 6.2 years during Study 729).
    Adverse event reporting additional description
    Data reported as TEAEs, defined as any AE that: • Was not present prior to receiving the first dose of study treatment in Study 729; or, • Was present prior to receiving the first dose of study treatment in Study 729 but the intensity increased after the first dose of study treatment in Study 729. Analysis was performed on the safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    LA:LA (Study 726:Study 729)
    Reporting group description
    		 Patients who received lanreotide Autogel 120 mg in core Study 726 and who continued to receive open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as LA:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.

    Reporting group title
    Total LA (Study 729)
    Reporting group description
    		 All patients treated with open label lanreotide Autogel 120 mg (LA) in extension Study 729.

    Reporting group title
    PB:LA (Study 726:Study 729)
    Reporting group description
    		 Patients who received placebo in core Study 726 and who received open label lanreotide Autogel 120 mg in extension Study 729. Note, all patients in extension Study 729 received the same dose of lanreotide Autogel (120 mg) once every 28 days. This arm is referred to as PB:LA to designate randomised treatment in core Study 726:open label treatment in extension Study 729.

    Serious adverse events
    		 LA:LA (Study 726:Study 729) Total LA (Study 729) PB:LA (Study 726:Study 729)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 42 (26.19%)
    25 / 89 (28.09%)
    14 / 47 (29.79%)
         number of deaths (all causes)
    2
    5
    3
         number of deaths resulting from adverse events
    1
    3
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour Pain
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 89 (1.12%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Cancer
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour Necrosis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 89 (1.12%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 89 (1.12%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face Oedema
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Reproductive system and breast disorders
    Ovarian Cyst
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural Effusion
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic Stenosis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Incisional Hernia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post Procedural Haematoma
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Restrictive Cardiomyopathy
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Infarction
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 89 (1.12%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stroke In Evolution
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 89 (1.12%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Eye disorders
    Retinal Vein Occlusion
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 89 (1.12%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual Impairment
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Adhesions
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 89 (1.12%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 89 (1.12%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 89 (1.12%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 89 (1.12%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 89 (4.49%)
    4 / 47 (8.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 89 (2.25%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 89 (2.25%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Prerenal Failure
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 89 (1.12%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Hepatitis Viral
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative Wound Infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte Imbalance
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 89 (1.12%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LA:LA (Study 726:Study 729) Total LA (Study 729) PB:LA (Study 726:Study 729)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 42 (76.19%)
    69 / 89 (77.53%)
    37 / 47 (78.72%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 89 (4.49%)
    3 / 47 (6.38%)
         occurrences all number
    1
    6
    5
    Hypertension
         subjects affected / exposed
    4 / 42 (9.52%)
    9 / 89 (10.11%)
    5 / 47 (10.64%)
         occurrences all number
    4
    9
    5
    General disorders and administration site conditions
    Injection Site Pain
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 89 (4.49%)
    3 / 47 (6.38%)
         occurrences all number
    1
    4
    3
    Asthenia
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 89 (4.49%)
    4 / 47 (8.51%)
         occurrences all number
    0
    4
    4
    Pyrexia
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 89 (3.37%)
    3 / 47 (6.38%)
         occurrences all number
    0
    5
    5
    Injection Site Nodule
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 89 (3.37%)
    3 / 47 (6.38%)
         occurrences all number
    0
    3
    3
    Fatigue
         subjects affected / exposed
    5 / 42 (11.90%)
    9 / 89 (10.11%)
    4 / 47 (8.51%)
         occurrences all number
    6
    12
    6
    Oedema Peripheral
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 89 (4.49%)
    1 / 47 (2.13%)
         occurrences all number
    4
    5
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 42 (7.14%)
    6 / 89 (6.74%)
    3 / 47 (6.38%)
         occurrences all number
    3
    9
    6
    Oropharyngeal Pain
         subjects affected / exposed
    3 / 42 (7.14%)
    5 / 89 (5.62%)
    2 / 47 (4.26%)
         occurrences all number
    3
    6
    3
    Dyspnoea
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 89 (3.37%)
    3 / 47 (6.38%)
         occurrences all number
    0
    3
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 42 (9.52%)
    4 / 89 (4.49%)
    0 / 47 (0.00%)
         occurrences all number
    5
    5
    0
    Investigations
    Weight Decreased
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 89 (4.49%)
    3 / 47 (6.38%)
         occurrences all number
    1
    6
    5
    Injury, poisoning and procedural complications
    Procedural Pain
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 89 (4.49%)
    3 / 47 (6.38%)
         occurrences all number
    1
    7
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 42 (9.52%)
    6 / 89 (6.74%)
    2 / 47 (4.26%)
         occurrences all number
    6
    8
    2
    Headache
         subjects affected / exposed
    2 / 42 (4.76%)
    6 / 89 (6.74%)
    4 / 47 (8.51%)
         occurrences all number
    2
    6
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 42 (7.14%)
    6 / 89 (6.74%)
    3 / 47 (6.38%)
         occurrences all number
    3
    7
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 42 (19.05%)
    23 / 89 (25.84%)
    15 / 47 (31.91%)
         occurrences all number
    28
    53
    25
    Nausea
         subjects affected / exposed
    7 / 42 (16.67%)
    13 / 89 (14.61%)
    6 / 47 (12.77%)
         occurrences all number
    15
    26
    11
    Constipation
         subjects affected / exposed
    5 / 42 (11.90%)
    9 / 89 (10.11%)
    4 / 47 (8.51%)
         occurrences all number
    8
    14
    6
    Abdominal Discomfort
         subjects affected / exposed
    3 / 42 (7.14%)
    5 / 89 (5.62%)
    2 / 47 (4.26%)
         occurrences all number
    5
    8
    3
    Dyspepsia
         subjects affected / exposed
    5 / 42 (11.90%)
    7 / 89 (7.87%)
    2 / 47 (4.26%)
         occurrences all number
    5
    9
    4
    Abdominal Distension
         subjects affected / exposed
    3 / 42 (7.14%)
    7 / 89 (7.87%)
    4 / 47 (8.51%)
         occurrences all number
    3
    10
    7
    Haemorrhoids
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 89 (3.37%)
    3 / 47 (6.38%)
         occurrences all number
    0
    3
    3
    Steatorrhoea
         subjects affected / exposed
    2 / 42 (4.76%)
    7 / 89 (7.87%)
    5 / 47 (10.64%)
         occurrences all number
    2
    7
    5
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 89 (4.49%)
    4 / 47 (8.51%)
         occurrences all number
    0
    4
    4
    Abdominal Pain
         subjects affected / exposed
    7 / 42 (16.67%)
    14 / 89 (15.73%)
    7 / 47 (14.89%)
         occurrences all number
    7
    16
    9
    Vomiting
         subjects affected / exposed
    7 / 42 (16.67%)
    12 / 89 (13.48%)
    5 / 47 (10.64%)
         occurrences all number
    8
    19
    11
    Abdominal Pain Upper
         subjects affected / exposed
    3 / 42 (7.14%)
    12 / 89 (13.48%)
    9 / 47 (19.15%)
         occurrences all number
    4
    13
    9
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    7 / 42 (16.67%)
    14 / 89 (15.73%)
    7 / 47 (14.89%)
         occurrences all number
    10
    19
    9
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 42 (11.90%)
    7 / 89 (7.87%)
    2 / 47 (4.26%)
         occurrences all number
    6
    9
    3
    Dry Skin
         subjects affected / exposed
    3 / 42 (7.14%)
    5 / 89 (5.62%)
    2 / 47 (4.26%)
         occurrences all number
    5
    7
    2
    Pruritus
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 89 (4.49%)
    3 / 47 (6.38%)
         occurrences all number
    1
    6
    5
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 89 (3.37%)
    0 / 47 (0.00%)
         occurrences all number
    3
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 42 (9.52%)
    10 / 89 (11.24%)
    6 / 47 (12.77%)
         occurrences all number
    6
    18
    12
    Neck Pain
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 89 (4.49%)
    1 / 47 (2.13%)
         occurrences all number
    3
    4
    1
    Myalgia
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 89 (3.37%)
    3 / 47 (6.38%)
         occurrences all number
    0
    4
    4
    Osteoporosis
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 89 (3.37%)
    3 / 47 (6.38%)
         occurrences all number
    0
    3
    3
    Back Pain
         subjects affected / exposed
    3 / 42 (7.14%)
    9 / 89 (10.11%)
    6 / 47 (12.77%)
         occurrences all number
    3
    13
    10
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 42 (7.14%)
    10 / 89 (11.24%)
    7 / 47 (14.89%)
         occurrences all number
    6
    13
    7
    Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 42 (9.52%)
    5 / 89 (5.62%)
    1 / 47 (2.13%)
         occurrences all number
    6
    7
    1
    Viral Infection
         subjects affected / exposed
    4 / 42 (9.52%)
    6 / 89 (6.74%)
    2 / 47 (4.26%)
         occurrences all number
    5
    7
    2
    Sinusitis
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 89 (3.37%)
    0 / 47 (0.00%)
         occurrences all number
    3
    3
    0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 42 (4.76%)
    7 / 89 (7.87%)
    5 / 47 (10.64%)
         occurrences all number
    2
    8
    6
    Nasopharyngitis
         subjects affected / exposed
    1 / 42 (2.38%)
    5 / 89 (5.62%)
    4 / 47 (8.51%)
         occurrences all number
    1
    10
    9
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 89 (4.49%)
    1 / 47 (2.13%)
         occurrences all number
    3
    4
    1
    Diabetes Mellitus
         subjects affected / exposed
    2 / 42 (4.76%)
    6 / 89 (6.74%)
    4 / 47 (8.51%)
         occurrences all number
    2
    6
    4
    Hypokalaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 89 (4.49%)
    4 / 47 (8.51%)
         occurrences all number
    0
    5
    5
    Decreased Appetite
         subjects affected / exposed
    4 / 42 (9.52%)
    8 / 89 (8.99%)
    4 / 47 (8.51%)
         occurrences all number
    5
    10
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Mar 2012
    • To confirm that an interim analysis was to be performed when all patients completed core Study 726 and that some statistical tests of efficacy were to be performed.
    22 Oct 2013
    • To increase the maximum expected duration of the study to approximately 8 years. • To confirm that a second interim analysis was to be performed in order to be able to provide a safety update report during the review procedure.

    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/26743120
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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