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    Clinical Trial Results:
    A 12-months, randomized, VA-assessor blinded, multicenter, controlled phase IV trial to investigate non inferiority of two treatment algorithms (discretion of the investigator vs. pro re nata) of 0.5 mg ranibizumab in patients with visual impairment due to diabetic macula edema

    Summary
    EudraCT number
    		 2014-002854-37
    Trial protocol
    		 DE  
    Global end of trial date
    08 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2018
    First version publication date
    20 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRFB002DDE26
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02366468
    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, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    08 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate that the mean average change of BCVA in patients with DME treated with ranibizumab injections at the discretion of the investigator and in accordance with disease activity criteria is non-inferior to current standard of care (PRN).
    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
    23 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 135
    Worldwide total number of subjects
    135
    EEA total number of subjects
    135
    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)
    59
    From 65 to 84 years
    76
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 a total of 135 patients were randomized and assigned in a 1:1 ratio to the treatment arms. Two patients (one patient in each treatment arm) did not have any post-baseline BCVA assessments and were not counted as "Started". Both patients were included in the safety evaluations.

    Pre-assignment
    Screening details
    		 At Screening, the eligibility criteria were performed.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Discretion of the investigator (DI)
    Arm description
    		 Investigational - ranibizumab 0.5 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    ranibizumab 0.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraocular use
    Dosage and administration details
    ranibizumab 0.5 mg, after initial monthly treatment until maximum BCVA and no signs or no further change of disease activity, the investigator treated patients at their own discretion. There were no strict recommendations for retreatment or scheduling of upcoming visits.

    Arm title
    		 Pro re nata (PRN)
    Arm description
    		 Standard of Care - ranibizumab 0.5 mg
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ranibizumab 0.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraocular use
    Dosage and administration details
    ranibizumab 0.5 mg, after initial monthly therapy until maximum BCVA and no signs or no further improvement of disease activity, patients were monitored every month and retreated if any signs of disease activity occurred

    Number of subjects in period 1 [1]
    		Discretion of the investigator (DI) Pro re nata (PRN)
    Started
    67
    66
    Full Analysis Set (FAS)
    67
    66
    Per Protocol Set (PPS)
    62
    61
    Completed
    62
    58
    Not completed
    5
    8
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    1
    4
         Adverse event, non-fatal
    2
    -
         Lost to follow-up
    2
    -
         not specified
    -
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two patients (one patient in each treatment arm) did not have any post-baseline BCVA assessments and were not counted as "Started". Both patients were included in the safety evaluations.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Discretion of the investigator (DI)
    Reporting group description
    		 Investigational - ranibizumab 0.5 mg

    Reporting group title
    Pro re nata (PRN)
    Reporting group description
    		 Standard of Care - ranibizumab 0.5 mg

    Reporting group values
    		 Discretion of the investigator (DI) Pro re nata (PRN) Total
    Number of subjects
    		 67 66 133
    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)
    		 29 30 59
        From 65-84 years
    		 38 36 74
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.6 ( 13.73 ) 65.0 ( 10.37 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 22 25 47
        Male
    		 45 41 86
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian|
    		 64 64 128
        Black|
    		 1 1 2
        Asian|
    		 0 1 1
        Other|
    		 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Discretion of the investigator (DI)
    Reporting group description
    		 Investigational - ranibizumab 0.5 mg

    Reporting group title
    Pro re nata (PRN)
    Reporting group description
    		 Standard of Care - ranibizumab 0.5 mg

    Primary: Mean average change from baseline in Best Corrected Visual Acuity (BCVA) of the study eye from month 1 to study treatment completion (Month 12)

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    End point title
    		 Mean average change from baseline in Best Corrected Visual Acuity (BCVA) of the study eye from month 1 to study treatment completion (Month 12)
    End point description
    BCVA was assessed as letters read using Early Treatment Diabetic Retinopathy Study (ETDRS) charts. The mean average change from baseline was defined as the difference between the average level of BCVA (ETDRS letters) over all post-baseline assessments from Month 1 to Month 12. A positive change represents an improvement in visual acuity
    End point type
    Primary
    End point timeframe
    Baseline, Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12
    End point values
    		 Discretion of the investigator (DI) Pro re nata (PRN)
    Number of subjects analysed
    67
    66
    Units: Letters
    arithmetic mean (standard deviation)
        Baseline (Day 1)|
    67.4 ( 9.52 )
    65.1 ( 9.59 )
        post baseline average over month 1 to month 12|
    73.5 ( 9.50 )
    73.8 ( 7.75 )
        Visit-averaged change from baseline|
    6.1 ( 6.54 )
    8.6 ( 6.45 )
    Statistical analysis title
    		 Change in Best Corrected Visual Acuity
    Statistical analysis description
    The primary objective was to demonstrate that the mean visit-averaged change from baseline of BCVA over month 1 to treatment completion for the DI arm was non-inferior to the PRN arm.
    Comparison groups
    Discretion of the investigator (DI) v Pro re nata (PRN)
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.04
         upper limit
    		 1.27
    Notes
    [1] - non-inferiority margin: -4 letters

    Secondary: Number of visits

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    End point title
    		 Number of visits
    End point description
    Mean number of visits during the study
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Discretion of the investigator (DI) Pro re nata (PRN)
    Number of subjects analysed
    67
    66
    Units: Visits
        arithmetic mean (standard deviation)
    12.7 ( 1.92 )
    12.9 ( 2.25 )
    No statistical analyses for this end point

    Secondary: Number of injections

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    End point title
    		 Number of injections
    End point description
    mean number of injections in the study eye during the study
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Discretion of the investigator (DI) Pro re nata (PRN)
    Number of subjects analysed
    67
    66
    Units: Injections
        arithmetic mean (standard deviation)
    8.4 ( 2.98 )
    7.8 ( 3.25 )
    No statistical analyses for this end point

    Secondary: Number of treatment free intervals

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    End point title
    		 Number of treatment free intervals
    End point description
    A treatment-free interval is the interval between the first NO treatment given when the reason for NO treatment given is one of the three stability criteria and the first subsequent YES treatment given after that.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Discretion of the investigator (DI) Pro re nata (PRN)
    Number of subjects analysed
    67
    66
    Units: Intervals
        arithmetic mean (standard deviation)
    1.6 ( 0.76 )
    1.7 ( 0.94 )
    No statistical analyses for this end point

    Secondary: Mean change in central subfield retinal thickness (CSRT)

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    End point title
    		 Mean change in central subfield retinal thickness (CSRT)
    End point description
    Evaluated by central reading center assessing OCT images
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Discretion of the investigator (DI) Pro re nata (PRN)
    Number of subjects analysed
    67
    66
    Units: μm
    arithmetic mean (standard deviation)
        Baseline|
    420.0 ( 114.98 )
    431.0 ( 128.13 )
        Month 12 (LOCF)|
    313.3 ( 61.21 )
    320.6 ( 85.27 )
        Change from Baseline to Month 12 (LOCF)|
    -106.7 ( 109.58 )
    -110.4 ( 101.97 )
    Statistical analysis title
    		 Mean change in CSRT to Month 12
    Comparison groups
    Discretion of the investigator (DI) v Pro re nata (PRN)
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.62
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.1
         upper limit
    		 28.56

    Secondary: Mean change of foveal center point thickness

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    End point title
    		 Mean change of foveal center point thickness
    End point description
    Evaluated by central reading center assessing OCT images
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Discretion of the investigator (DI) Pro re nata (PRN)
    Number of subjects analysed
    67
    66
    Units: μm
    arithmetic mean (standard deviation)
        Baseline|
    398.8 ( 144.10 )
    405.0 ( 138.06 )
        Month 12 - LOCF|
    273.3 ( 84.85 )
    280.6 ( 105.44 )
        Change from Baseline to Month 12 (LOCF)|
    -125.6 ( 142.69 )
    -124.4 ( 113.29 )
    Statistical analysis title
    		 Mean change of foveal center point thickness
    Comparison groups
    Discretion of the investigator (DI) v Pro re nata (PRN)
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.925
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.66
         upper limit
    		 30.59

    Secondary: Change in diabetic retinopathy study (DRS) retinopathy scale

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    End point title
    		 Change in diabetic retinopathy study (DRS) retinopathy scale
    End point description
    Evaluated by central reading center scoring fundus photography
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Discretion of the investigator (DI) Pro re nata (PRN)
    Number of subjects analysed
    67
    66
    Units: Participants
        > 2 steps improvement
    7
    7
        2 steps improvement
    3
    4
        1 step improvement
    6
    1
        0 steps
    38
    34
        1 step loss
    4
    4
        2 steps loss
    2
    1
        > 2 steps loss
    1
    5
        Missing
    6
    10
    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 are reported in this record from 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
    20.0
    Reporting groups
    Reporting group title
    Ranibizumab 0.5 mg PRN
    Reporting group description
    		 Ranibizumab 0.5 mg PRN

    Reporting group title
    Ranibizumab 0.5 mg DI
    Reporting group description
    		 Ranibizumab 0.5 mg DI

    Serious adverse events
    		 Ranibizumab 0.5 mg PRN Ranibizumab 0.5 mg DI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 67 (32.84%)
    13 / 68 (19.12%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acoustic neuroma
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Behcet's syndrome
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary nitrogen increased
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (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
    Contusion
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (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
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin abrasion
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve injury
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         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
    2 / 67 (2.99%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart valve incompetence
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eyelid function disorder
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenitis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         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 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (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
    Bronchitis
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (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
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (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
    		 Ranibizumab 0.5 mg PRN Ranibizumab 0.5 mg DI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 67 (64.18%)
    44 / 68 (64.71%)
    Investigations
    Glycosylated haemoglobin increased
         subjects affected / exposed
    7 / 67 (10.45%)
    5 / 68 (7.35%)
         occurrences all number
    7
    6
    Intraocular pressure increased
         subjects affected / exposed
    6 / 67 (8.96%)
    8 / 68 (11.76%)
         occurrences all number
    6
    19
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 67 (0.00%)
    4 / 68 (5.88%)
         occurrences all number
    0
    5
    Hypertension
         subjects affected / exposed
    7 / 67 (10.45%)
    3 / 68 (4.41%)
         occurrences all number
    10
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 67 (1.49%)
    4 / 68 (5.88%)
         occurrences all number
    1
    8
    Eye disorders
    Cataract
         subjects affected / exposed
    5 / 67 (7.46%)
    2 / 68 (2.94%)
         occurrences all number
    6
    4
    Conjunctival haemorrhage
         subjects affected / exposed
    14 / 67 (20.90%)
    13 / 68 (19.12%)
         occurrences all number
    20
    21
    Corneal erosion
         subjects affected / exposed
    4 / 67 (5.97%)
    4 / 68 (5.88%)
         occurrences all number
    4
    4
    Eye irritation
         subjects affected / exposed
    5 / 67 (7.46%)
    1 / 68 (1.47%)
         occurrences all number
    10
    2
    Eye pain
         subjects affected / exposed
    4 / 67 (5.97%)
    7 / 68 (10.29%)
         occurrences all number
    4
    16
    Foreign body sensation in eyes
         subjects affected / exposed
    1 / 67 (1.49%)
    6 / 68 (8.82%)
         occurrences all number
    1
    10
    Macular oedema
         subjects affected / exposed
    5 / 67 (7.46%)
    5 / 68 (7.35%)
         occurrences all number
    5
    10
    Ocular discomfort
         subjects affected / exposed
    4 / 67 (5.97%)
    4 / 68 (5.88%)
         occurrences all number
    6
    15
    Visual acuity reduced
         subjects affected / exposed
    8 / 67 (11.94%)
    7 / 68 (10.29%)
         occurrences all number
    18
    16
    Visual impairment
         subjects affected / exposed
    2 / 67 (2.99%)
    4 / 68 (5.88%)
         occurrences all number
    3
    6
    Vitreous floaters
         subjects affected / exposed
    5 / 67 (7.46%)
    3 / 68 (4.41%)
         occurrences all number
    7
    4
    Vitreous haemorrhage
         subjects affected / exposed
    2 / 67 (2.99%)
    6 / 68 (8.82%)
         occurrences all number
    3
    8
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 67 (2.99%)
    4 / 68 (5.88%)
         occurrences all number
    2
    4
    Pain in extremity
         subjects affected / exposed
    1 / 67 (1.49%)
    4 / 68 (5.88%)
         occurrences all number
    1
    4
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    4 / 67 (5.97%)
    1 / 68 (1.47%)
         occurrences all number
    5
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    18 / 67 (26.87%)
    19 / 68 (27.94%)
         occurrences all number
    22
    24

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2016
    This amendment was issued to stop further recruitment to the study. The reason to stop recruitment was new and relevant scientific evidence regarding treatment patterns with ranibizumab which did not justify continuing the trial with newly included patients.

    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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    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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