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    Clinical Trial Results:
    An open-label Extended Clinical Protocol of ranibizumab to evaluate Safety and Efficacy in rare VEGF driven ocular diseases

    Summary
    EudraCT number
    2013-001421-55
    Trial protocol
    FR  
    Global end of trial date
    13 May 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    25 May 2017
    First version publication date
    25 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRFB002GFR02
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01908816
    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
    13 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the 2-year safety of ranibizumab as assessed by type, rate and severity of serious and non-serious, ocular and non-ocular, adverse events
    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
    26 Sep 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
    France: 270
    Worldwide total number of subjects
    270
    EEA total number of subjects
    270
    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)
    153
    From 65 to 84 years
    106
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    open-label, single arm study evaluating the safety of 0.5 mg ranibizumab. Patients received individualized ranibizumab intravitreal injections based on evidence of disease activity. The study was early terminated due to low recruitment that hampered to address the primary endpoint of the study

    Pre-assignment
    Screening details
    A total of 196 patients completed the visit at Month 3 (M3), 127 completed the visit at M12 and 16 at M24. Due to the early termination of the study no patient completed the planned visit at M36. The mean time to premature discontinuation was 11.2 months, that encompasses the time between the first injection and the study discontinuation

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CNV (Choroidal Neovascularization)
    Arm description
    All patients received 0.5 mg ranibizumab IVT injection
    Arm type
    Experimental

    Investigational medicinal product name
    ranibizumab 0.5 mg
    Investigational medicinal product code
    RFB002
    Other name
    Lucentis
    Pharmaceutical forms
    Intravesical solution/solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.5mg

    Arm title
    ME (Macular Edema)
    Arm description
    All patients received 0.5 mg ranibizumab IVT injection
    Arm type
    Experimental

    Investigational medicinal product name
    Ranibizumab 0.5 mg)
    Investigational medicinal product code
    RFB002
    Other name
    Lucentis®
    Pharmaceutical forms
    Intravesical solution/solution for injection
    Routes of administration
    Intracervical use
    Dosage and administration details
    0.5mg

    Arm title
    RI/NVG (Rubeosis Iridis and Neovacular Glaucoma)
    Arm description
    All patients received 0.5 mg ranibizumab IVT injection
    Arm type
    Experimental

    Investigational medicinal product name
    Ranibizumab 0.5 mg)
    Investigational medicinal product code
    RFB002
    Other name
    Lucentis
    Pharmaceutical forms
    Intravesical solution
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.5mg

    Arm title
    PDR/V
    Arm description
    (Proliferative Diabetic Retinopathy requiring Vitrectomy). All patients received 0.5 mg ranibizumab IVT injection
    Arm type
    Experimental

    Investigational medicinal product name
    Ranibizumab 0.5 mg
    Investigational medicinal product code
    RFB002
    Other name
    Lucentis
    Pharmaceutical forms
    Intravesical solution/solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.5mg

    Number of subjects in period 1
    CNV (Choroidal Neovascularization) ME (Macular Edema) RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) PDR/V
    Started
    93
    84
    58
    35
    Completed
    0
    0
    0
    0
    Not completed
    93
    84
    58
    35
         Early termination
    87
    60
    43
    28
         Unsatisfactory therapeutic effect
    1
    13
    1
    -
         Adverse event, serious fatal
    1
    -
    7
    1
         Subject's no longer requires study drug
    -
    -
    -
    1
         Consent withdrawn by subject
    -
    4
    2
    2
         Protocol deviation
    1
    2
    1
    1
         Lost to follow-up
    3
    5
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CNV (Choroidal Neovascularization)
    Reporting group description
    All patients received 0.5 mg ranibizumab IVT injection

    Reporting group title
    ME (Macular Edema)
    Reporting group description
    All patients received 0.5 mg ranibizumab IVT injection

    Reporting group title
    RI/NVG (Rubeosis Iridis and Neovacular Glaucoma)
    Reporting group description
    All patients received 0.5 mg ranibizumab IVT injection

    Reporting group title
    PDR/V
    Reporting group description
    (Proliferative Diabetic Retinopathy requiring Vitrectomy). All patients received 0.5 mg ranibizumab IVT injection

    Reporting group values
    CNV (Choroidal Neovascularization) ME (Macular Edema) RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) PDR/V Total
    Number of subjects
    93 84 58 35 270
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    71 38 15 29 153
        From 65-84 years
    22 43 35 6 106
        85 years and over
    0 3 8 0 11
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    49.7 ± 16.85 64.5 ± 13.99 70.9 ± 13.02 56.5 ± 9.86 -
    Gender, Male/Female
    Units: Subjects
        Female
    48 35 26 17 126
        Male
    45 49 32 18 144
    Subject analysis sets

    Subject analysis set title
    Ranibizumab 0.5 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients received 0.5 mg ranibizumab IVT injection

    Subject analysis sets values
    Ranibizumab 0.5 mg
    Number of subjects
    56
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    153
        From 65-84 years
    106
        85 years and over
    11
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    59.7 ± 16.62
    Gender, Male/Female
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    CNV (Choroidal Neovascularization)
    Reporting group description
    All patients received 0.5 mg ranibizumab IVT injection

    Reporting group title
    ME (Macular Edema)
    Reporting group description
    All patients received 0.5 mg ranibizumab IVT injection

    Reporting group title
    RI/NVG (Rubeosis Iridis and Neovacular Glaucoma)
    Reporting group description
    All patients received 0.5 mg ranibizumab IVT injection

    Reporting group title
    PDR/V
    Reporting group description
    (Proliferative Diabetic Retinopathy requiring Vitrectomy). All patients received 0.5 mg ranibizumab IVT injection

    Subject analysis set title
    Ranibizumab 0.5 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients received 0.5 mg ranibizumab IVT injection

    Primary: Number of participants with Adverse Events as a Measure of Safety and Tolerability

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    End point title
    Number of participants with Adverse Events as a Measure of Safety and Tolerability [1]
    End point description
    Frequency of Adverse Events (AEs) and Serious Adverse Events (SAEs) for ocular and non-ocular events. Due to early termination, only descriptive analysis was conducted.
    End point type
    Primary
    End point timeframe
    24 months
    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: Due to early termination, no statistical analysis was planned for this primary endpoint
    End point values
    CNV (Choroidal Neovascularization) ME (Macular Edema) RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) PDR/V
    Number of subjects analysed
    93
    84
    58
    35
    Units: Participants
        Non- serious adverse events
    2
    21
    1
    0
        Serious adverse events
    11
    15
    31
    14
        Death
    1
    0
    7
    1
    No statistical analyses for this end point

    Secondary: Change from baseline Best Corrected Visual Acuity (BCVA) for patients with Choroidal Neovascularization (CNV) and Macular Edema (ME)

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    End point title
    Change from baseline Best Corrected Visual Acuity (BCVA) for patients with Choroidal Neovascularization (CNV) and Macular Edema (ME) [2]
    End point description
    BCVA will be tested using the ETDRS, the Snellen or Monoyer scales. VA measurements will be preferentially taken in a sitting position at an initial test distance of 4 meters using ETDRS charts. The overall BCVA score will be calculated using the BCVA worksheet which will be kept in the source data and the score will be recorded in the eCRF. ETDRS, Snellen and Monoyer VA measurements will be transformed in logMAR to be analyzed.
    End point type
    Secondary
    End point timeframe
    3 months, 12 months
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to early termination, no statistical analysis was planned for this endpoint
    End point values
    CNV (Choroidal Neovascularization) ME (Macular Edema)
    Number of subjects analysed
    93
    84
    Units: Letters
    arithmetic mean (standard deviation)
        3 Month (n=74,69,33,17)
    7.3 ± 14.47
    4.5 ± 11.61
        12 Month (n=47,39,26,14)
    5.7 ± 12.08
    5.2 ± 16.46
    No statistical analyses for this end point

    Secondary: Average change of neovascularization extension for patients with neovascular glaucoma

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    End point title
    Average change of neovascularization extension for patients with neovascular glaucoma
    End point description
    Change of the extent of iris neovascularization using “Teich and Walsh grading system” using iris photography
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    Ranibizumab 0.5 mg
    Number of subjects analysed
    56
    Units: Teich and Walsh grading
        3 Month,Grade 0 (n=31)
    12
        3 Month, Grade 1 (n=31)
    6
        3 Month, Grade 2 (n=31)
    8
        3 Month, Grade 3 (n=31)
    3
        3 Month, Grade 4 (n=31)
    2
        12 Month, Grade 0 (n=25)
    11
        12 Month, Grade 1 (n=25)
    4
        12 Month, Grade 2 (n=25)
    2
        12 Month, Grade 3 (n=25)
    4
        12 Month, Grade 4 (n=25)
    4
    No statistical analyses for this end point

    Secondary: Proportion of patient with Vitreous Cavity Hemorrhage occurrence for patient with proliferative retinopathy

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    End point title
    Proportion of patient with Vitreous Cavity Hemorrhage occurrence for patient with proliferative retinopathy [3]
    End point description
    Occurrence of postoperative vitreous cavity hemorrhage
    End point type
    Secondary
    End point timeframe
    3 months, 12 month
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to early termination, no statistical analysis was planned for this endpoint
    End point values
    PDR/V
    Number of subjects analysed
    34
    Units: Participants
        3 Month Absent (n=17)
    14
        3 Month Present (n=17)
    3
        12 Month Absent (n=13)
    12
        12 Month Present (n=13)
    1
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in change in central retinal thickness

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    End point title
    Mean Change From Baseline in change in central retinal thickness [4]
    End point description
    CRT in micrometers assessed by Optical Tomography (OCT) at each single study visit. A reduction is thickness indicates an improvement is the lesion area
    End point type
    Secondary
    End point timeframe
    3 months, 12 month
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to early termination, no statistical analysis was planned for this endpoint
    End point values
    CNV (Choroidal Neovascularization) ME (Macular Edema)
    Number of subjects analysed
    93
    84
    Units: μm
    arithmetic mean (standard deviation)
        3 Month (n=74, 67)
    -54.4 ± 104.55
    -84.4 ± 178.28
        12 Month (n=45, 40)
    -56.4 ± 69.82
    -102 ± 220
    No statistical analyses for this end point

    Secondary: Proportion of patients with angiographic leakage

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    End point title
    Proportion of patients with angiographic leakage [5]
    End point description
    Angiography was taken via fluorescein angiography. Any increases of angiographic leakage was counted between baseline and month 3. Also any decreases of angiographic leakage was counted between baseline and 3 month.
    End point type
    Secondary
    End point timeframe
    3 months, 12 month
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to early termination, no statistical analysis was planned for this endpoint
    End point values
    CNV (Choroidal Neovascularization) ME (Macular Edema) PDR/V
    Number of subjects analysed
    93
    84
    34
    Units: Participants
        3 Month Absent (n=6,6,1)
    3
    3
    1
        3 Month Present (n=6,6,1)
    3
    3
    0
        12 Month Absent (n=5,1,0)
    3
    1
    0
        12 Month Present (5,1,0)
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Ranibizumab injection

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    End point title
    Ranibizumab injection
    End point description
    Number of ranibizumab injections needed by decreased visual acuity and/or increasing retinal thickness in 3 months of observation period
    End point type
    Secondary
    End point timeframe
    3 months, 12 month
    End point values
    CNV (Choroidal Neovascularization) ME (Macular Edema) RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) PDR/V
    Number of subjects analysed
    93
    84
    58
    35
    Units: Number of injections
    arithmetic mean (standard deviation)
        3 Month (n=75,70,34,17)
    2.5 ± 1.03
    2.7 ± 0.88
    1.7 ± 0.79
    1.6 ± 1
        12 Month (n=44,38,21,14)
    3.8 ± 2.34
    3.9 ± 2.17
    3 ± 1.96
    1.7 ± 1.44
    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
    20.0
    Reporting groups
    Reporting group title
    Ranibizumab 0.5 mg
    Reporting group description
    Ranibizumab 0.5 mg

    Serious adverse events
    Ranibizumab 0.5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    71 / 270 (26.30%)
         number of deaths (all causes)
    9
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Arterial disorder
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Choroid melanoma (Study eye)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug ineffective (Study eye)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    2 / 270 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle rupture
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Intraocular pressure increased (Study eye)
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 270 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    4 / 270 (1.48%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Akinesia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 270 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Anterior chamber fibrin (Study eye)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blindness (Both eyes)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cataract (Contralateral eye)
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cataract (Study eye)
         subjects affected / exposed
    2 / 270 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Glaucoma (Contralateral eye)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glaucoma (Study eye)
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Macular detachment (Both eyes)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Macular fibrosis (Study eye)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ocular hypertension (Both eyes)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ocular hypertension (Study eye)
         subjects affected / exposed
    9 / 270 (3.33%)
         occurrences causally related to treatment / all
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    Retinal artery occlusion (Both eyes)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retinal detachment (Study eye)
         subjects affected / exposed
    4 / 270 (1.48%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Retinal pigment epithelial tear (Study eye)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retinal tear (Study eye)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Visual acuity reduced (Both eyes)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Visual acuity reduced (Study eye)
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Vitreous adhesions (Contralateral eye)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vitreous adhesions (Study eye)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vitreous haemorrhage (Contralateral eye)
         subjects affected / exposed
    2 / 270 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Vitreous haemorrhage (Study eye)
         subjects affected / exposed
    5 / 270 (1.85%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Duodenal obstruction
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal angiodysplasia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal dysplasia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pancreatic mass
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephroangiosclerosis
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthropathy
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    4 / 270 (1.48%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Corneal abscess (Study eye)
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Influenza
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syphilis
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Ranibizumab 0.5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    144 / 270 (53.33%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3
    Hypertension
         subjects affected / exposed
    4 / 270 (1.48%)
         occurrences all number
    4
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3
    Inappropriate schedule of drug administration (Study eye)
         subjects affected / exposed
    37 / 270 (13.70%)
         occurrences all number
    38
    Incorrect product storage (Study eye)
         subjects affected / exposed
    11 / 270 (4.07%)
         occurrences all number
    17
    Investigations
    Blood urea increased
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 270 (4.81%)
         occurrences all number
    19
    Dizziness
         subjects affected / exposed
    5 / 270 (1.85%)
         occurrences all number
    5
    Eye disorders
    Cataract (Study eye)
         subjects affected / exposed
    4 / 270 (1.48%)
         occurrences all number
    4
    Conjunctival haemorrhage (Study eye)
         subjects affected / exposed
    5 / 270 (1.85%)
         occurrences all number
    5
    Eye pain (Study eye)
         subjects affected / exposed
    21 / 270 (7.78%)
         occurrences all number
    25
    Dry eye (Study eye)
         subjects affected / exposed
    4 / 270 (1.48%)
         occurrences all number
    4
    Eye pruritus (Study eye)
         subjects affected / exposed
    4 / 270 (1.48%)
         occurrences all number
    4
    Ocular hyperaemia (Study eye)
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3
    Ocular hypertension (Study eye)
         subjects affected / exposed
    5 / 270 (1.85%)
         occurrences all number
    5
    Punctate keratitis (Study eye)
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3
    Ulcerative keratitis (Study eye)
         subjects affected / exposed
    5 / 270 (1.85%)
         occurrences all number
    6
    Vision blurred (Study eye)
         subjects affected / exposed
    5 / 270 (1.85%)
         occurrences all number
    5
    Visual acuity reduced (Contralateral eye)
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3
    Visual acuity reduced (Study eye)
         subjects affected / exposed
    7 / 270 (2.59%)
         occurrences all number
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3
    Drug ineffective (Study eye)
         subjects affected / exposed
    31 / 270 (11.48%)
         occurrences all number
    31
    Fatigue
         subjects affected / exposed
    9 / 270 (3.33%)
         occurrences all number
    9
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 270 (1.85%)
         occurrences all number
    5
    Back pain
         subjects affected / exposed
    5 / 270 (1.85%)
         occurrences all number
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 270 (1.85%)
         occurrences all number
    5
    Conjunctivitis (Study eye)
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3
    Conjunctivitis (Both eyes)
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3
    Influenza
         subjects affected / exposed
    5 / 270 (1.85%)
         occurrences all number
    5
    Sinusitis
         subjects affected / exposed
    4 / 270 (1.48%)
         occurrences all number
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 270 (1.48%)
         occurrences all number
    6
    Urinary tract infection
         subjects affected / exposed
    3 / 270 (1.11%)
         occurrences all number
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2013
    due to several modifications in this version, the ethic committees asked for a new version of the protocol, with corrections highlighted. This version was used at the beginning of the project
    16 Dec 2013
    the wording of the inclusion criterion n°2 was changed from “Patient with diagnosis of active choroidal neovascularization (CNV) secondary to any causes (except wAMD, PM and PXE), involving the center of the fovea, confirmed by complete ocular examination of the study eye” to “Patient with diagnosis of active choroidal neovascularization (CNV) secondary to any causes (except wAMD, PM and PXE), involving the center of the macula, confirmed by complete ocular examination of the study eye”. This version V5 was issued after 13 patients had been recruited.
    05 Feb 2014
    this modification of the protocol authorized the investigators to use of the data of ophthalmic examinations present in the medical record of the patient when these examinations were realized within 14 days before the visit of selection (V1), if the patient was eligible. This modification was implemented to avoid the repetition of potentially invasive ophthalmological examination (e.g. angiography) if already performed recently. This decreased the number of ophthalmologic examinations for as they were not necessary from a medical perspective.
    28 May 2015
    this amendment was issued to collect additional safety and efficacy data from year 2 to year 3 in patients treated with ranibizumab for rare ocular VEGF-driven diseases. This one-year extension of the study would also respond to an unmet medical need for licensed therapies that could be used to treat rare ocular VEGF-driven diseases affecting visual function. Indeed, extending the follow-up allowed treating with ranibizumab patients with such diseases. Consistently, changes related to this one-year extension were done throughout the protocol (e.g., additional secondary objectives, analysis of additional secondary variables).
    31 Aug 2015
    this amendment was issued to provide clarifications about assessing and treating the patients. These clarifications (listed below) primarily provided more details about the administration of treatment and the assessment of visual acuity : - Change to Instructions for prescribing and taking study treatment (section 5.5.4): clarification that the interval between 2 ranibizumab injections should not been shorter than 28 days. - Changes to Patient demographics/other baseline characteristics (section 6.2): clarification that day of birth was recorded in the eCRF. - Changes to Best-corrected visual acuity (BCVA) (section 6.4.1): clarification that an ETDRS BCVA assessment could be performed at 2 meters. “If the ETDRS BCVA measurement was performed at 2 meters instead of 4 meters (using 4 meters ETDRS scales), a correction was applied by removing 15 letters (3 lines) to the ETDRS score obtained at 2 meters.” - Changes to Informed consent (section 11.2): clarification that it was not the responsibility of the investigator to submit informed consent form for CPP approval. These changes of protocol were not considered to have an impact on the study population or on the patients’ safety.

    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.
    As the study was early terminated, no conclusion could be drawn from this study. The data should be interpreted with cautious as less than half of the patients included in the study (47.0%) completed the visit at Month 12.
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