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    Clinical Trial Results:
    Safety and Efficacy of Brimonidine Posterior Segment Drug Delivery System in Patients with Geographic Atrophy Secondary to Age-related Macular Degeneration (BEACON Study)

    Summary
    EudraCT number
    2013-003320-36
    Trial protocol
    DE   IT  
    Global end of trial date
    30 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    11 May 2019
    First version publication date
    11 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    190342-038
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02087085
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Allergan Ltd.
    Sponsor organisation address
    1st Floor, Marlow International, The Parkway, Marlow Buckinghamshire, United Kingdom, SL7 1YL
    Public contact
    Clinical Trials Registry Team, Allergan plc, 001 877‐277‐8566, IR-CTRegistration@allergan.com
    Scientific contact
    Therapeutic Area, Head, Allergan plc, 001 862-261-7000, IR-CTRegistration@Allergan.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
    30 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the safety and efficacy of the brimonidine intravitreal implant in participants with geographic atrophy (GA) due to age-related macular degeneration.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 May 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 55
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    United States: 149
    Country: Number of subjects enrolled
    Australia: 34
    Worldwide total number of subjects
    310
    EEA total number of subjects
    127
    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)
    17
    From 65 to 84 years
    242
    85 years and over
    51

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 576 participants were screened, and 310 participants were enrolled and randomised to receive either 400 µg brimonidine implant or sham treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    400 µg Brimonidine Implant
    Arm description
    400 µg brimonidine implant in the study eye, administered by intravitreal injections using the Brimonidine Drug Delivery System (Brimo DDS®) applicator every 3 months from Baseline (Day 1) through Month 21.
    Arm type
    Experimental

    Investigational medicinal product name
    Brimonidine free base
    Investigational medicinal product code
    AGN-190342
    Other name
    Pharmaceutical forms
    Implant
    Routes of administration
    Intravitreal use
    Dosage and administration details
    400 µg brimonidine implant in the study eye using Brimo DDS® applicator on Day 1, and every 3 months through Month 21.

    Arm title
    Sham
    Arm description
    Sham treatment (control) in the study eye, administered by intravitreal injections using a needleless drug delivery system (DDS) applicator every 3 months from Baseline (Day 1) through Month 21.
    Arm type
    Sham comparator

    Investigational medicinal product name
    Sham
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Implant
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Sham treatment with needleless applicator (no implant) to the study eye on Day 1, and every 3 months through Month 21.

    Number of subjects in period 1
    400 µg Brimonidine Implant Sham
    Started
    154
    156
    Completed
    34
    40
    Not completed
    120
    116
         Adverse Event
    10
    14
         Withdrawal by Subject
    9
    11
         Study Terminated by Sponsor
    87
    80
         Lost to follow-up
    6
    4
         Other Miscellaneous Reasons
    3
    4
         Lack of efficacy
    4
    3
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    400 µg Brimonidine Implant
    Reporting group description
    400 µg brimonidine implant in the study eye, administered by intravitreal injections using the Brimonidine Drug Delivery System (Brimo DDS®) applicator every 3 months from Baseline (Day 1) through Month 21.

    Reporting group title
    Sham
    Reporting group description
    Sham treatment (control) in the study eye, administered by intravitreal injections using a needleless drug delivery system (DDS) applicator every 3 months from Baseline (Day 1) through Month 21.

    Reporting group values
    400 µg Brimonidine Implant Sham Total
    Number of subjects
    154 156 310
    Age categorical
    Units: Subjects
        18-64 years
    13 4 17
        65-84 years
    116 126 242
        85 years and over
    25 26 51
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    76.9 ( 7.89 ) 77.0 ( 7.24 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    101 91 192
        Male
    53 65 118
    Race/Ethnicity, Customized
    Units: Subjects
        White
    153 156 309
        Black or African American
    1 0 1
    Geographic Atrophy (GA) Lesion Area by Fundus Autofluorescence (FAF)
    GA lesion area was measured in mm^2 by FAF and analysis of FAF images was performed by the central reading centre. Modified intent-to-treat (mITT) population included all randomised and treated participants with baseline and at least 1 postbaseline assessment for GA lesion area by FAF.
    Units: millimetres squared (mm^2)
        arithmetic mean (standard deviation)
    ( ) ( ) -
    Subject analysis sets

    Subject analysis set title
    400 µg Brimonidine Implant
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    400 µg brimonidine implant in the study eye, administered by intravitreal injections using the Brimonidine Drug Delivery System (Brimo DDS®) applicator every 3 months from Baseline (Day 1) through Month 21.

    Subject analysis set title
    Sham
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Sham treatment (control) in the study eye, administered by intravitreal injections using a needleless DDS applicator every 3 months from Baseline (Day 1) through Month 21.

    Subject analysis sets values
    400 µg Brimonidine Implant Sham
    Number of subjects
    149
    154
    Age categorical
    Units: Subjects
        18-64 years
        65-84 years
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Sex: Female, Male
    Units: Subjects
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        White
        Black or African American
    Geographic Atrophy (GA) Lesion Area by Fundus Autofluorescence (FAF)
    GA lesion area was measured in mm^2 by FAF and analysis of FAF images was performed by the central reading centre. Modified intent-to-treat (mITT) population included all randomised and treated participants with baseline and at least 1 postbaseline assessment for GA lesion area by FAF.
    Units: millimetres squared (mm^2)
        arithmetic mean (standard deviation)
    5.1611 ( 3.7016 )
    5.4761 ( 3.5961 )

    End points

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    End points reporting groups
    Reporting group title
    400 µg Brimonidine Implant
    Reporting group description
    400 µg brimonidine implant in the study eye, administered by intravitreal injections using the Brimonidine Drug Delivery System (Brimo DDS®) applicator every 3 months from Baseline (Day 1) through Month 21.

    Reporting group title
    Sham
    Reporting group description
    Sham treatment (control) in the study eye, administered by intravitreal injections using a needleless drug delivery system (DDS) applicator every 3 months from Baseline (Day 1) through Month 21.

    Subject analysis set title
    400 µg Brimonidine Implant
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    400 µg brimonidine implant in the study eye, administered by intravitreal injections using the Brimonidine Drug Delivery System (Brimo DDS®) applicator every 3 months from Baseline (Day 1) through Month 21.

    Subject analysis set title
    Sham
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Sham treatment (control) in the study eye, administered by intravitreal injections using a needleless DDS applicator every 3 months from Baseline (Day 1) through Month 21.

    Primary: Change From Baseline in Geographic Atrophy (GA) Lesion Area of the Study Eye as Assessed by Fundus Autofluorescence (FAF) at Month 24

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    End point title
    Change From Baseline in Geographic Atrophy (GA) Lesion Area of the Study Eye as Assessed by Fundus Autofluorescence (FAF) at Month 24
    End point description
    GA lesion area was measured in mm^2 by FAF in the study eye and was quantified by the central reading centre. The study eye was defined as the eye that met inclusion/exclusion criteria with the worst standard Best Correct Visual Acuity (BCVA). If the BCVA in both eyes was similar the right eye was selected as the study eye. A positive change from baseline indicates an increase in size of GA lesion area (worsening; disease progression). Mixed model for repeated measures (MMRM) was used for analysis. Participants from the modified intent-to-treat (mITT) population, all randomised and treated participants with baseline and at least 1 postbaseline assessment for GA lesion area by FAF, with data available for analysis at Month 24.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) to Month 24
    End point values
    400 µg Brimonidine Implant Sham
    Number of subjects analysed
    86
    90
    Units: mm^2
        least squares mean (standard error)
    3.1455 ( 0.1377 )
    3.5044 ( 0.1359 )
    Statistical analysis title
    400 µg Brimonidine Implant vs Sham
    Comparison groups
    400 µg Brimonidine Implant v Sham
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.047 [1]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.3589
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7132
         upper limit
    -0.0047
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1804
    Notes
    [1] - MMRM model included treatment group, study region, analysis visit and treatment-by-visit interaction as factors and baseline value and baseline value-by-analysis visit interaction as covariates.

    Secondary: Change From Baseline in Standard Best Corrected Visual Acuity (BCVA) Score as Assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) Chart at Month 24

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    End point title
    Change From Baseline in Standard Best Corrected Visual Acuity (BCVA) Score as Assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) Chart at Month 24
    End point description
    BCVA was measured using an eye chart (ETDRS) and was reported as the number of letters read correctly (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). The study eye was defined as the eye that met inclusion/exclusion criteria with the worst standard BCVA. If the BCVA in both eyes was similar the right eye was selected as the study eye. A positive change from baseline indicates an improvement and a negative change from baseline indicates a worsening. MMRM was used for analysis. Participants from the mITT population, all randomised and treated participants with baseline and at least 1 postbaseline assessment for GA lesion area by FAF, with data available for analysis for this endpoint at Month 24.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Month 24
    End point values
    400 µg Brimonidine Implant Sham
    Number of subjects analysed
    81
    82
    Units: letters read correctly
        least squares mean (standard error)
    -10.9 ( 1.0 )
    -9.7 ( 1.0 )
    Statistical analysis title
    400 µg Brimonidine Implant vs Sham
    Comparison groups
    400 µg Brimonidine Implant v Sham
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.39 [2]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.9
         upper limit
    1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4
    Notes
    [2] - MMRM model included treatment group, study region, analysis visit and treatment-by-visit interaction as factors and baseline value and baseline value-by-analysis visit interaction as covariates.

    Secondary: Change From Baseline in Low Luminance BCVA Score as Assessed by ETDRS Chart at Month 24

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    End point title
    Change From Baseline in Low Luminance BCVA Score as Assessed by ETDRS Chart at Month 24
    End point description
    Low Luminance BCVA was measured by placing a 2.0 log unit neutral density filter over the best correction for that eye and having the participant read the normally illuminated ETDRS chart and was reported as the number of letters read correctly (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). The study eye was defined as the eye that met inclusion/exclusion criteria with the worst standard BCVA. If the BCVA in both eyes was similar the right eye was selected as the study eye. A positive change from baseline indicates an improvement and a negative change from baseline indicates a worsening. MMRM was used for analysis. Participants from the mITT population, all randomised and treated participants with baseline and at least 1 postbaseline assessment for GA lesion area by FAF, with data available for analysis for this endpoint at Month 24.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Month 24
    End point values
    400 µg Brimonidine Implant Sham
    Number of subjects analysed
    81
    82
    Units: letters read correctly
        least squares mean (standard error)
    -8.1 ( 1.0 )
    -6.7 ( 1.0 )
    Statistical analysis title
    400 µg Brimonidine Implant vs Sham
    Comparison groups
    400 µg Brimonidine Implant v Sham
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.301 [3]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.2
         upper limit
    1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4
    Notes
    [3] - MMRM model included treatment group, study region, analysis visit and treatment-by-visit interaction as factors and baseline value and baseline value-by-analysis visit interaction as covariates.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug to date of last visit (up to approximately 33 months)
    Adverse event reporting additional description
    Safety population included all participants who received at least 1 administration of study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    400 µg Brimonidine Implant
    Reporting group description
    400 µg brimonidine implant in the study eye, administered by intravitreal injections using the Brimonidine Drug Delivery System (DDS) every 3 months from Baseline (Day 1) through Month 21.

    Reporting group title
    Sham
    Reporting group description
    Sham treatment (control) in the study eye, administered by intravitreal injections using a needleless DDS Applicator every 3 months from Baseline (Day 1) through Month 21.

    Serious adverse events
    400 µg Brimonidine Implant Sham
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 154 (31.17%)
    37 / 156 (23.72%)
         number of deaths (all causes)
    5
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 154 (1.30%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 154 (1.30%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    2 / 154 (1.30%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Desmoplastic melanoma
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal melanoma
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip neoplasm malignant stage unspecified
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine adenocarcinoma
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal gland cancer
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 154 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Uterine prolapse
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 154 (0.65%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 154 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 154 (1.30%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural intestinal perforation
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flail chest
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 154 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 154 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 154 (1.95%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 154 (1.95%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    3 / 154 (1.95%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 154 (1.95%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 154 (1.30%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    2 / 154 (1.30%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Brain stem ischaemia
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia alzheimer's type
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Encephalopathy
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    2 / 154 (1.30%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    2 / 154 (1.30%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anterior capsule contraction
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hiatus hernia
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spigelian hernia
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Intertrigo
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder outlet obstruction
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    2 / 154 (1.30%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acquired claw toe
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 154 (0.65%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 154 (1.95%)
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    400 µg Brimonidine Implant Sham
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    79 / 154 (51.30%)
    61 / 156 (39.10%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    5 / 154 (3.25%)
    10 / 156 (6.41%)
         occurrences all number
    6
    11
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 154 (5.19%)
    11 / 156 (7.05%)
         occurrences all number
    8
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 154 (5.19%)
    4 / 156 (2.56%)
         occurrences all number
    8
    5
    Eye disorders
    Vitreous floaters
         subjects affected / exposed
    29 / 154 (18.83%)
    1 / 156 (0.64%)
         occurrences all number
    30
    1
    Conjunctival haemorrhage
         subjects affected / exposed
    21 / 154 (13.64%)
    11 / 156 (7.05%)
         occurrences all number
    27
    13
    Visual impairment
         subjects affected / exposed
    12 / 154 (7.79%)
    6 / 156 (3.85%)
         occurrences all number
    16
    11
    Eye pain
         subjects affected / exposed
    11 / 154 (7.14%)
    9 / 156 (5.77%)
         occurrences all number
    11
    11
    Visual acuity reduced
         subjects affected / exposed
    9 / 154 (5.84%)
    6 / 156 (3.85%)
         occurrences all number
    11
    10
    Dry eye
         subjects affected / exposed
    8 / 154 (5.19%)
    6 / 156 (3.85%)
         occurrences all number
    12
    12
    Ocular discomfort
         subjects affected / exposed
    8 / 154 (5.19%)
    1 / 156 (0.64%)
         occurrences all number
    8
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 154 (7.79%)
    12 / 156 (7.69%)
         occurrences all number
    18
    17
    Urinary tract infection
         subjects affected / exposed
    3 / 154 (1.95%)
    15 / 156 (9.62%)
         occurrences all number
    3
    17

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2014
    Amendment 1: The study design was updated to reflect changes in timing of selected procedures, additional data collection in the nonstudy eye (3-field confocal scanning laser ophthalmoscopy (cSLO) exams), and the addition of blood samples for modelling of disease progression by gene expression analysis. In addition, roflumilast was added as a prohibited medication and clarifications were made throughout the protocol.
    27 Aug 2014
    Amendment 2: Updates were made to the inclusion and exclusion criteria (specifically the addition of inclusion criterion #6 requiring the presence of drusen as assessed with fundus photography and/or spectral-domain optical coherence tomography (SD-OCT) at Screening and the modification of exclusion criterion #14 to exclude participants with a history of glaucoma who might had had visual field deficits). The study design was updated to reflect the addition of corneal curvature assessment, the removal of blood draw for pharmacokinetic (PK) at Months 9 and 24, and the requirement that complete ophthalmic examinations include: external examination of the eye and adnexa, screening for eyelid/pupil responsiveness, slit-lamp biomicroscopy, indirect ophthalmoscopy, dilated fundus examination, and intraocular pressure (IOP) assessment. The following other efficacy measure was added: “GA lesion area growth in the fellow eye, as assessed with FAF and quantified by the central reading centre (CRC),” and scotopic microperimetry was changed to scotopic/mesopic microperimetry.
    30 Sep 2014
    Amendment 3: The number of sites was revised from approximately 15 to 20 to approximately 15 to 30 and inclusion criteria were updated to reflect looser restrictions for participant eligibility in order to facilitate participant recruitment. In addition, visit windows for corneal curvature assessments were adjusted for participant convenience, and other minor clarifications were made.
    08 Oct 2014
    Amendment 4: The maximum lesion size was increased from 12.5 mm^2 to 18mm^2. The visit window for Screening Visit 2 was changed from -19 to -2 days to -20 to -2 days for participant and investigator convenience. In addition, several corrections and clarifications were made.
    14 Jan 2015
    Amendment 5: Several revisions were made to reflect that microperimetry would only be conducted at selected sites in participants who qualified and consented to the procedure in order to ease participant recruitment; loss of retinal sensitivity was removed from the clinical hypotheses and retinal sensitivity was changed to the other efficacy endpoint, rather than a secondary efficacy endpoint. In addition, a possible interim analysis of the first 50% of participants that completed Month 18 was added in order to facilitate earlier project planning.
    13 May 2015
    Amendment 6: To facilitate participant recruitment, the number of sites was increased from approximately 30 to approximately 40 and the inclusion criterion requiring that the study eye have a BCVA better than or equal to 55 letters (20/80 Snellen equivalent) was changed to require a BCVA better than or equal to 45 letters (20/125 Snellen equivalent). A second interim analysis was planned to be carried out when 100% of participants had completed Month 18. Updates were also made to reflect that standard and low luminance BCVA would be assessed in both eyes, rather than the study eye only, at Baseline and Months 12 and 24, and that these BCVA assessments would be done prior to pupil dilation, as pupil dilation temporarily reduces visual acuity. In addition, cSLO quantitative fundus autofluorescence (Qfaf) (central field) was changed to be an assessment performed in participants who participated in the microperimetry procedure only, and in the study eye only, rather than both eyes.
    23 May 2017
    Amendment 7: Updates were made to reflect the following changes to efficacy measures and analyses: area of reticular drusen was changed to presence or absence of reticular drusen (given difficulty of measuring the area), the primary efficacy analysis method was changed from an analysis of covariance to an MMRM in order to attain greater statistical power, near-IR measurement was changed from 7-field to 3-field, genotyping was changed from analysis of specific changes to genome-wide variations, use of a Goldmann applanation tonometer for IOP measurements was changed to recommended instead of required, last observation carried forward analyses were removed, per-protocol population was removed, and it was specified that analyses performed on the mITT population would be based on the randomised treatment. In addition, the interim analysis that was planned to be carried out when 100% of participants completed Month 18 was dropped from the planned analyses. Several clarifications and corrections were also made throughout the protocol.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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