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    Clinical Trial Results:
    A 24-month, Phase 3b, randomized, double-masked, multicenter study assessing the efficacy and safety of two treatment regimens of 0.5 mg ranibizumab intravitreal injections guided by functional and/or anatomical criteria, in patients with neovascular age-related macular degeneration (OCTAVE)

    Summary
    EudraCT number
    		 2011-004959-39
    Trial protocol
    		 CZ   LT   ES   IE   DE   SK   AT   IT   GB   GR   SE   FI   PT   HU   NL   FR  
    Global end of trial date
    09 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jul 2016
    First version publication date
    24 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRFB002A2405
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01780935
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    09 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The original primary objective was to evaluate the effectiveness of 2 treatment regimens by assessing the average best corrected visual acuity (BCVA) change from Month 4 to Month 12 compared to Month 3 based on both BCVA stability in each treatment group and comparison of the 2 treatment groups. For the analysis of these objectives a reference margin of 2 letters was planned to be applied.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jun 2013
    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
    Argentina: 18
    Country: Number of subjects enrolled
    Austria: 26
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    Colombia: 12
    Country: Number of subjects enrolled
    Czech Republic: 58
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 59
    Country: Number of subjects enrolled
    United Kingdom: 67
    Country: Number of subjects enrolled
    Greece: 20
    Country: Number of subjects enrolled
    Guatemala: 10
    Country: Number of subjects enrolled
    Hungary: 107
    Country: Number of subjects enrolled
    Ireland: 12
    Country: Number of subjects enrolled
    Italy: 47
    Country: Number of subjects enrolled
    Lithuania: 21
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Netherlands: 19
    Country: Number of subjects enrolled
    Panama: 2
    Country: Number of subjects enrolled
    Portugal: 32
    Country: Number of subjects enrolled
    Slovakia: 44
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    Switzerland: 32
    Country: Number of subjects enrolled
    Turkey: 18
    Worldwide total number of subjects
    671
    EEA total number of subjects
    555
    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)
    78
    From 65 to 84 years
    527
    85 years and over
    66

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study was originally designed to be a 24-month Phase 3b, randomized, double-masked, multicenter study, with 26 visits planned. Assuming an approximate 20% screen failure rate, approximately 840 patients needed to be screened to have 670 eligible in the study. A total of 671 patients were randomized.

    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
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RBZ 0.5 mg: VA only (Group I)
    Arm description
    		 RBZ 0.5 mg: Visual Acuity (VA) only (Group I) 0.5 mg intravitreal injections of ranibizumab with retreatment based on best-corrected visual acuity (BCVA) loss due to neovascular (wet) age-related macular degeneration (nAMD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    ranibizumab
    Investigational medicinal product code
    RFB002
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    RBZ 0.5 mg intravitreal injections monthly

    Arm title
    		 RBZ 0.5 mg: VA and/or OCT (Group II)
    Arm description
    		 RBZ 0.5 mg: VA and/or OCT (Group II) 0.5 mg intravitreal injections of ranibizumab with retreatment based on best-corrected visual acuity (BCVA)loss due to neovascular (wet) age-related macular degeneration (nAMD) and/or signs of wet AMD disease activity on optical coherence tomography (OCT).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ranibizumab
    Investigational medicinal product code
    RFB002
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    RBZ 0.5 mg intravitreal injections monthly

    Number of subjects in period 1
    		RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Started
    335
    336
    Completed
    0
    0
    Not completed
    335
    336
         Adverse event, serious fatal
    1
    6
         Physician decision
    1
    1
         Patient withdrew consent
    8
    9
         Adverse event, non-fatal
    2
    4
         Protocol deviation
    -
    1
         Lost to follow-up
    2
    6
         early termination/administrative problems
    321
    309

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RBZ 0.5 mg: VA only (Group I)
    Reporting group description
    		 RBZ 0.5 mg: Visual Acuity (VA) only (Group I) 0.5 mg intravitreal injections of ranibizumab with retreatment based on best-corrected visual acuity (BCVA) loss due to neovascular (wet) age-related macular degeneration (nAMD)

    Reporting group title
    RBZ 0.5 mg: VA and/or OCT (Group II)
    Reporting group description
    		 RBZ 0.5 mg: VA and/or OCT (Group II) 0.5 mg intravitreal injections of ranibizumab with retreatment based on best-corrected visual acuity (BCVA)loss due to neovascular (wet) age-related macular degeneration (nAMD) and/or signs of wet AMD disease activity on optical coherence tomography (OCT).

    Reporting group values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II) Total
    Number of subjects
    		 335 336 671
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 47 31 78
        From 65-84 years
    		 263 264 527
        85 years and over
    		 25 41 66
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73.9 ± 7.86 75.3 ± 7.91 -
    Gender, Male/Female
    Units: participants
        Male
    		 122 142 264
        Female
    		 213 194 407

    End points

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    End points reporting groups
    Reporting group title
    RBZ 0.5 mg: VA only (Group I)
    Reporting group description
    		 RBZ 0.5 mg: Visual Acuity (VA) only (Group I) 0.5 mg intravitreal injections of ranibizumab with retreatment based on best-corrected visual acuity (BCVA) loss due to neovascular (wet) age-related macular degeneration (nAMD)

    Reporting group title
    RBZ 0.5 mg: VA and/or OCT (Group II)
    Reporting group description
    		 RBZ 0.5 mg: VA and/or OCT (Group II) 0.5 mg intravitreal injections of ranibizumab with retreatment based on best-corrected visual acuity (BCVA)loss due to neovascular (wet) age-related macular degeneration (nAMD) and/or signs of wet AMD disease activity on optical coherence tomography (OCT).

    Primary: Average best-corrected visual acuity (BCVA) (letters) change from Month 3 to Month 4 to Month 12

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    End point title
    		 Average best-corrected visual acuity (BCVA) (letters) change from Month 3 to Month 4 to Month 12 [1]
    End point description
    Visual acuity (VA) was assessed during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like VA testing charts at a testing distance of 4 meters. This outcome measure describes the difference between the Visual Acuity averaged across all visits from Month 3 to Month 12 Level of VA (Letters) of the Study Eye. The treatment regimen up to Month 3 is the same in both treatment groups.
    End point type
    Primary
    End point timeframe
    Month 3, Month 4, Month 12
    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: No statistical analysis was conducted due to early termination
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    335
    336
    Units: Letters correctly read
        arithmetic mean (standard deviation)
    0.1 ± 6.79
    1 ± 7.25
    No statistical analyses for this end point

    Secondary: Change from Baseline in Visual Acuity (Letters) of the Study Eye over time

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    End point title
    		 Change from Baseline in Visual Acuity (Letters) of the Study Eye over time
    End point description
    Visual acuity (VA) was assessed using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like VA testing charts at a testing distance of 4 meters. This outcome measure describes the difference between the Visual Acuity averaged from Baseline to Month 12 Level of VA (Letters) of the Study Eye.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    335
    336
    Units: letters correctly read
        arithmetic mean (standard deviation)
    6.7 ± 13.48
    8.3 ± 13.53
    No statistical analyses for this end point

    Secondary: Gain of equal or more than 1, 5, 10, or 15 letters in Visual Acuity of the Study Eye from Baseline, at Month 12 and 24

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    End point title
    		 Gain of equal or more than 1, 5, 10, or 15 letters in Visual Acuity of the Study Eye from Baseline, at Month 12 and 24
    End point description
    During the course of the study, the use of optical coherence tomography (OCT)-guided therapy became a standard of care accepted by health authorities and the ophthalmology community in the treatment of neovascular (wet) age-related macular degeneration (nAMD), Novartis decided on 08-Oct-2014 the early termination of the study for futility. Therefore the 12-month cutoff date was not reached and the related analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12 and 24
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: number of letters
        number (not applicable)
    Notes
    [2] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    [3] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    No statistical analyses for this end point

    Secondary: Loss of less than 5, 10, and 15 letters in Visual Acuity in the Study Eye from Baseline, at Month 12 and 24

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    End point title
    		 Loss of less than 5, 10, and 15 letters in Visual Acuity in the Study Eye from Baseline, at Month 12 and 24
    End point description
    During the course of the study, the use of optical coherence tomography (OCT)-guided therapy became a standard of care accepted by health authorities and the ophthalmology community in the treatment of neovascular (wet) age-related macular degeneration (nAMD), Novartis decided on 08-Oct-2014 the early termination of the study for futility. Therefore the 12-month cutoff date was not reached and the related analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12 and 24
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: numbers of letters
        number (not applicable)
    Notes
    [4] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    [5] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    No statistical analyses for this end point

    Secondary: Visual Acuity of 73 letters or more in the Study Eye at Month 12 and 24

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    End point title
    		 Visual Acuity of 73 letters or more in the Study Eye at Month 12 and 24
    End point description
    During the course of the study, the use of optical coherence tomography (OCT)-guided therapy became a standard of care accepted by health authorities and the ophthalmology community in the treatment of neovascular (wet) age-related macular degeneration (nAMD), Novartis decided on 08-Oct-2014 the early termination of the study for futility. Therefore the 12-month cutoff date was not reached and the related analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: number of letters
        number (not applicable)
    Notes
    [6] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    [7] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    No statistical analyses for this end point

    Secondary: Average Visual Acuity change from Month 3 to Month 4 through Month 24 in the Study Eye

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    End point title
    		 Average Visual Acuity change from Month 3 to Month 4 through Month 24 in the Study Eye
    End point description
    During the course of the study, the use of optical coherence tomography (OCT)-guided therapy became a standard of care accepted by health authorities and the ophthalmology community in the treatment of neovascular (wet) age-related macular degeneration (nAMD), Novartis decided on 08-Oct-2014 the early termination of the study for futility. Therefore the 12-month cutoff date was not reached and the related analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Month 3 to Month 24
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: number of letters
        number (not applicable)
    Notes
    [8] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    [9] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    No statistical analyses for this end point

    Secondary: Average Visual Acuity change from baseline to Month 1 through Month 12 and 24 in the Study Eye

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    End point title
    		 Average Visual Acuity change from baseline to Month 1 through Month 12 and 24 in the Study Eye
    End point description
    During the course of the study, the use of optical coherence tomography (OCT)-guided therapy became a standard of care accepted by health authorities and the ophthalmology community in the treatment of neovascular (wet) age-related macular degeneration (nAMD), Novartis decided on 08-Oct-2014 the early termination of the study for futility. Therefore the 12-month cutoff date was not reached and the related analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12 and 24
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: number of letters
        number (not applicable)
    Notes
    [10] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    [11] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    No statistical analyses for this end point

    Secondary: Change from Baseline in Central Sub-Field Thickness (CSFT) and Central Sub-Field Volume (CSFV) of the Study Eye over time

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    End point title
    		 Change from Baseline in Central Sub-Field Thickness (CSFT) and Central Sub-Field Volume (CSFV) of the Study Eye over time
    End point description
    During the course of the study, the use of optical coherence tomography (OCT)-guided therapy became a standard of care accepted by health authorities and the ophthalmology community in the treatment of neovascular (wet) age-related macular degeneration (nAMD), Novartis decided on 08-Oct-2014 the early termination of the study for futility. Therefore the 12-month cutoff date was not reached and the related analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12 and 24
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: number of letters
        number (not applicable)
    Notes
    [12] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    [13] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    No statistical analyses for this end point

    Secondary: Dry retina in the Study Eye on OCT at Month 12 and 24

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    End point title
    		 Dry retina in the Study Eye on OCT at Month 12 and 24
    End point description
    During the course of the study, the use of optical coherence tomography (OCT)-guided therapy became a standard of care accepted by health authorities and the ophthalmology community in the treatment of neovascular (wet) age-related macular degeneration (nAMD), Novartis decided on 08-Oct-2014 the early termination of the study for futility. Therefore the 12-month cutoff date was not reached and the related analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: number of occurences
        number (not applicable)
    Notes
    [14] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    [15] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    No statistical analyses for this end point

    Secondary: Change from Baseline in lesion size and morphology based on fluorescein angiography at Month 12 and 24

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    End point title
    		 Change from Baseline in lesion size and morphology based on fluorescein angiography at Month 12 and 24
    End point description
    During the course of the study, the use of optical coherence tomography (OCT)-guided therapy became a standard of care accepted by health authorities and the ophthalmology community in the treatment of neovascular (wet) age-related macular degeneration (nAMD), Novartis decided on 08-Oct-2014 the early termination of the study for futility. Therefore the 12-month cutoff date was not reached and the related analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12 and 24
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: lesion size
        number (not applicable)
    Notes
    [16] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    [17] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    No statistical analyses for this end point

    Secondary: Treatment patterns over time in both treatment arms

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    End point title
    		 Treatment patterns over time in both treatment arms
    End point description
    During the course of the study, the use of optical coherence tomography (OCT)-guided therapy became a standard of care accepted by health authorities and the ophthalmology community in the treatment of neovascular (wet) age-related macular degeneration (nAMD), Novartis decided on 08-Oct-2014 the early termination of the study for futility. Therefore the 12-month cutoff date was not reached and the related analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12 and 24
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: treatment patterns
        number (not applicable)
    Notes
    [18] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    [19] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    No statistical analyses for this end point

    Secondary: Change from Baseline in the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) scores over time

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    End point title
    		 Change from Baseline in the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) scores over time
    End point description
    During the course of the study, the use of optical coherence tomography (OCT)-guided therapy became a standard of care accepted by health authorities and the ophthalmology community in the treatment of neovascular (wet) age-related macular degeneration (nAMD), Novartis decided on 08-Oct-2014 the early termination of the study for futility. Therefore the 12-month cutoff date was not reached and the related analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12 and 24
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    0 [20]
    0 [21]
    Units: scores on a scale
        number (not applicable)
    Notes
    [20] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    [21] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    No statistical analyses for this end point

    Secondary: Frequency and severity of ocular and non-ocular adverse events over time

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    End point title
    		 Frequency and severity of ocular and non-ocular adverse events over time
    End point description
    During the course of the study, the use of optical coherence tomography (OCT)-guided therapy became a standard of care accepted by health authorities and the ophthalmology community in the treatment of neovascular (wet) age-related macular degeneration (nAMD), Novartis decided on 08-Oct-2014 the early termination of the study for futility. Therefore the 12-month cutoff date was not reached and the related analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Screening to Month 12 and 24
    End point values
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: frequency of adverse events
        number (not applicable)
    Notes
    [22] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    [23] - Early termination - the 12-month cutoff date not reached and the related analysis was not performed
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    RBZ 0.5 mg: VA only (Group I)
    Reporting group description
    		 RBZ 0.5 mg: VA only (Group I)

    Reporting group title
    RBZ 0.5 mg: VA and/or OCT (Group II)
    Reporting group description
    		 RBZ 0.5 mg: VA and/or OCT (Group II)

    Serious adverse events
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 334 (8.98%)
    45 / 336 (13.39%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of ampulla of Vater
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesothelioma malignant
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to pleura
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to skin
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 334 (0.00%)
    2 / 336 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast calcifications
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 334 (0.00%)
    2 / 336 (0.60%)
         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
    Bronchitis chronic
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 334 (0.30%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Visual acuity tests abnormal (Study eye)
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 334 (0.30%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 334 (0.30%)
    4 / 336 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (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 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 334 (0.00%)
    3 / 336 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         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
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery occlusion
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (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
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis post varicella (Study eye)
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 334 (0.60%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Choroidal haemorrhage (Study eye)
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic ischaemic neuropathy (Fellow untreated eye)
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery embolism (Study eye)
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual acuity reduced (Study eye)
         subjects affected / exposed
    1 / 334 (0.30%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ischaemic
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic hepatitis
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 334 (0.60%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 334 (0.30%)
    2 / 336 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 334 (0.00%)
    3 / 336 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 334 (0.00%)
    1 / 336 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 334 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 RBZ 0.5 mg: VA only (Group I) RBZ 0.5 mg: VA and/or OCT (Group II)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 334 (19.76%)
    49 / 336 (14.58%)
    Investigations
    Intraocular pressure increased (Study eye)
         subjects affected / exposed
    12 / 334 (3.59%)
    21 / 336 (6.25%)
         occurrences all number
    16
    35
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 334 (5.39%)
    15 / 336 (4.46%)
         occurrences all number
    21
    16
    Eye disorders
    Conjunctival haemorrhage (Study eye)
         subjects affected / exposed
    19 / 334 (5.69%)
    10 / 336 (2.98%)
         occurrences all number
    20
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    24 / 334 (7.19%)
    11 / 336 (3.27%)
         occurrences all number
    25
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Sep 2013
    Amendment 1, issued after the inclusion of 12% of the patients, aimed to provide a more extensive risk-benefit assessment and to clarify some aspects of the protocol following Health Authority review. Minor revisions were done to the inclusion and exclusion criteria and clarifications were provided around assessing and treating the patient and the statistical analysis. Also, the amendment introduced the use of the pre-filled syringe (PFS) of ranibizumab. The safety and efficacy of ranibizumab administered with the PFS was not considered different from ranibizumab supplied in a vial.

    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.
    The use of OCT guided therapy in the treatment of nAMD became a standard of care during the study course. Early termination was therefore decided. The 12 month cutoff date was not reached and planned analyses were not performed.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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