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    Clinical Trial Results:
    A MULTICENTER, RANDOMIZED, DOUBLE-MASKED, 3 PARALLEL ARMS,PLACEBO CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF NOVA22007 1MG/ML (CICLOSPORIN/CYCLOSPORINE) EYE DROPS,EMULSION ADMINISTERED IN PAEDIATRIC PATIENTS WITH ACTIVE SEVERE VERNAL KERATOCONJUNCTIVITIS WITH SEVERE KERATITIS

    Summary
    EudraCT number
    		 2012-005060-10
    Trial protocol
    		 HU   IT   DE   PT   ES   GR   HR   FR  
    Global end of trial date
    01 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Apr 2023
    First version publication date
    07 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NVG09B113
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01751126
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Santen Sas
    Sponsor organisation address
    Genavenir IV, 1 rue Pierre Fontaine , Evry, France,
    Public contact
    Mourad Amrane, Santen SAS, 331 69874022, mourad.amrane@santen.com
    Scientific contact
    Mourad Amrane, Santen SAS, 331 69874022, mourad.amrane@santen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000575-PIP01-09
    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
    01 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to compare the efficacy of two different dosing regimens of NOVA22007 (1mg/ml ciclosporin/cyclosporine) eye drops, emulsion versus placebo (vehicle of the formulation) administered four times a day in patients with severe VKC after 4 months of treatment.
    Protection of trial subjects
    Dexamethasone 0.1% eye drops provided by the sponsor will be dispensed by the investigator to the patient during the course of the study treatment only in case of keratitis worsening of at least one grade on the modified Oxford scale or maintained during 2 months at the entry level and/or symptom worsening of at least 1 centimeter on at least one of the four symptoms along with the worsening of the mean of the 4 symptoms or maintenance at the entry level of the mean VAS of the 4 symptoms. The dosing instructions will be 1 drop 4 times daily for 5 days and a maximum of 2 courses between two scheduled visits during the treatment period and a maximum of 4 courses between two scheduled visits during the 8 month safety period. The rescue therapy will have to be given at least 30 minutes before or after the study medication. To reduce the systemic absorption a nasolacrimal occlusion by compression of lacrimal ducts should be applied after the instillation. The rescue therapy need and prescription will have to be documented by the investigator during a visit. If the patient is unable to reach the investigator for a visit the patient will be allowed to use unpreserved artificial tears taken up to 4 times a day until a visit is scheduled.
    Background therapy
    		 None
    Evidence for comparator
    		 A placebo arm was deemed appropriate as there is no acknowledged standard treatment for VKC. Also the design of the study allows a reduced number of children that have to be recruited for a well-recognized rare disease. The placebo arm will not be a strict untreated arm as the vehicle will be administered and also the investigator will have the possibility to give a rescue medication: dexamethasone 0.1% 4 times a day for 5 days provided that the patient satisfies the condition for rescue medication prescription: in case of keratitis worsening of at least one grade on the Modified Oxford Scale or maintained during 2 months at the entry level and/or symptom worsening of at least 1 centimeter on at least one of the four symptoms along with the worsening of the mean of the 4 symptoms or maintenance at the entry level of the mean VAS of the 4 symptoms.
    Actual start date of recruitment
    29 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Croatia: 2
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    India: 34
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    168
    EEA total number of subjects
    100
    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)
    127
    Adolescents (12-17 years)
    41
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 169 patients were randomized into the study. These patients were recruited in 11 countries and a total of 101 patients were from Europe. One participant from the High dose regimen withdrew at the first week of randomization and not related to study medication. Therefore, the Full Analysis Set (FAS) consisted of 168 patients.

    Period 1
    Period 1 title
    Period I
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NOVA22007 Ciclosporing 4 times at day
    Arm description
    		 One drop of ciclosporin (NOVA22007) 1 mg/ml 4 times a day as monotherapy (morning, noon, afternoon and evening).
    Arm type
    		 Experimental

    Investigational medicinal product name
    NOVA22007
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear drops, emulsion
    Routes of administration
    Ocular use
    Dosage and administration details
    For the group receiving the study medication 4 times a day 1 drop of the study medication NOVA22007 1 mg/mL CsA eye drops, emulsion in each eye 4 times daily: in the morning, at noon, in the afternoon and the evening.

    Arm title
    		 NOVA22007 Ciclosporin/Placebo twice daily
    Arm description
    		 One drop of ciclosporin (NOVA22007) 1mg/ml twice a day and one drop of placebo twice a day (active study treatment morning and evening and placebo noon and afternoon) as monotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NOVA22007
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, emulsion
    Routes of administration
    Ocular use
    Dosage and administration details
    • For the group receiving the study medication twice a day 1 drop of the study medication NOVA22007 1mg/ml CsA eye drops, emulsion in each eye in the morning and evening and 1 drop of the placebo (vehicle of the study medication) at noon and in the afternoon.

    Arm title
    		 Placebo
    Arm description
    		 One drop of placebo 4 times a day as monotherapy (morning, noon, afternoon and evening).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, emulsion
    Routes of administration
    Ocular use
    Dosage and administration details
    The placebo was the NOVA22007 vehicle which is a sterile, drug-free, cationic ophthalmic oil-in-water emulsion containing 0 mg/mL CsA. The formulation of placebo was exactly the same formulation as the NOVA22007 but excluded the active substance. For the group receiving the placebo 4 times a day 1 drop of the placebo in each eye 4 times daily: in the morning, at noon, in the afternoon and evening.

    Number of subjects in period 1
    		NOVA22007 Ciclosporing 4 times at day NOVA22007 Ciclosporin/Placebo twice daily Placebo
    Started
    56
    54
    58
    Completed
    50
    43
    49
    Not completed
    6
    11
    9
         Patient decision unrelated to AE
    2
    3
    2
         Adverse event, non-fatal
    2
    -
    2
         Other
    -
    1
    -
         Investigator decision
    1
    1
    -
         Lost to follow-up
    -
    1
    -
         Lack of efficacy
    1
    5
    5
    Period 2
    Period 2 title
    Period II
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NOVA22007 Ciclosporing 4 times at day
    Arm description
    		 One drop of ciclosporin (NOVA22007) 1 mg/ml 4 times a day as monotherapy (morning, noon, afternoon and evening).
    Arm type
    		 Experimental

    Investigational medicinal product name
    NOVA22007
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, emulsion
    Routes of administration
    Ocular use
    Dosage and administration details
    For the group receiving the study medication 4 times a day 1 drop of the study medication NOVA22007 1 mg/mL CsA eye drops, emulsion in each eye 4 times daily: in the morning, at noon, in the afternoon and the evening.

    Arm title
    		 NOVA22007 Ciclosporin/Placebo twice daily
    Arm description
    		 One drop of ciclosporin (NOVA22007) 1mg/ml twice a day and one drop of placebo twice a day (active study treatment morning and evening and placebo noon and afternoon) as monotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NOVA22007
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, emulsion
    Routes of administration
    Ocular use
    Dosage and administration details
    For the group receiving the study medication twice a day 1 drop of the study medication NOVA22007 1mg/ml CsA eye drops, emulsion in each eye in the morning and evening and 1 drop of the placebo (vehicle of the study medication) at noon and in the afternoon.

    Number of subjects in period 2
    		NOVA22007 Ciclosporing 4 times at day NOVA22007 Ciclosporin/Placebo twice daily
    Started
    72
    70
    Completed
    72
    70

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NOVA22007 Ciclosporing 4 times at day
    Reporting group description
    		 One drop of ciclosporin (NOVA22007) 1 mg/ml 4 times a day as monotherapy (morning, noon, afternoon and evening).

    Reporting group title
    NOVA22007 Ciclosporin/Placebo twice daily
    Reporting group description
    		 One drop of ciclosporin (NOVA22007) 1mg/ml twice a day and one drop of placebo twice a day (active study treatment morning and evening and placebo noon and afternoon) as monotherapy.

    Reporting group title
    Placebo
    Reporting group description
    		 One drop of placebo 4 times a day as monotherapy (morning, noon, afternoon and evening).

    Reporting group values
    		 NOVA22007 Ciclosporing 4 times at day NOVA22007 Ciclosporin/Placebo twice daily Placebo Total
    Number of subjects
    		 56 54 58 168
    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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Children (4-18 years)
    Units: years
        arithmetic mean (standard deviation)
    		 9.1 ± 3.3 9.6 ± 3.4 8.9 ± 3.2 -
    Gender categorical
    Units: Subjects
        Female
    		 12 12 12 36
        Male
    		 44 42 46 132

    End points

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    End points reporting groups
    Reporting group title
    NOVA22007 Ciclosporing 4 times at day
    Reporting group description
    		 One drop of ciclosporin (NOVA22007) 1 mg/ml 4 times a day as monotherapy (morning, noon, afternoon and evening).

    Reporting group title
    NOVA22007 Ciclosporin/Placebo twice daily
    Reporting group description
    		 One drop of ciclosporin (NOVA22007) 1mg/ml twice a day and one drop of placebo twice a day (active study treatment morning and evening and placebo noon and afternoon) as monotherapy.

    Reporting group title
    Placebo
    Reporting group description
    		 One drop of placebo 4 times a day as monotherapy (morning, noon, afternoon and evening).
    Reporting group title
    NOVA22007 Ciclosporing 4 times at day
    Reporting group description
    		 One drop of ciclosporin (NOVA22007) 1 mg/ml 4 times a day as monotherapy (morning, noon, afternoon and evening).

    Reporting group title
    NOVA22007 Ciclosporin/Placebo twice daily
    Reporting group description
    		 One drop of ciclosporin (NOVA22007) 1mg/ml twice a day and one drop of placebo twice a day (active study treatment morning and evening and placebo noon and afternoon) as monotherapy.

    Subject analysis set title
    LogMAR - High Dose Regimen
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This group has the randomized population (SS).

    Subject analysis set title
    LogMAR - Low Dose Regimen
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This group has the randomized population (SS).

    Subject analysis set title
    LogMAR-Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This group has the randomized population (SS).

    Subject analysis set title
    Change From Baseline in LogMARHigh Dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This group has the randomized population (SS).

    Subject analysis set title
    Change From Baseline in LogMARLow Dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This group has the randomized population (SS).

    Subject analysis set title
    Change From Baseline in LogMARPlacebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This group has the randomized population (SS).

    Primary: Composite efficacy score

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    End point title
    		 Composite efficacy score
    End point description
    End point type
    Primary
    End point timeframe
    over the 4months
    End point values
    		 NOVA22007 Ciclosporing 4 times at day NOVA22007 Ciclosporin/Placebo twice daily Placebo
    Number of subjects analysed
    56
    54
    58
    Units: penalties adjusted CFS
        arithmetic mean (standard deviation)
    2.06 ± 1.44
    1.93 ± 1.37
    1.34 ± 1.22
    Statistical analysis title
    		 Superiority test1
    Statistical analysis description
    Claim superiority of the active treatment over placebo in the primary endpoint.
    Comparison groups
    NOVA22007 Ciclosporing 4 times at day v Placebo
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 1.27
    Notes
    [1] - ANCOVA with treatment as well the baseline CFS and the exposure to VKC seasons (Hochberg procedure)
    Statistical analysis title
    		 Superiority test2
    Statistical analysis description
    Claim superiority of the active treatment- low dose over placebo in the primary endpoint.
    Comparison groups
    Placebo v NOVA22007 Ciclosporin/Placebo twice daily
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 1.18
    Notes
    [2] - ANCOVA with treatment as well the baseline CFS and the exposure to VKC seasons (Hochberg procedure)

    Secondary: Number of Courses of Rescue Medication in Period I

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    End point title
    		 Number of Courses of Rescue Medication in Period I
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 4-Month
    End point values
    		 NOVA22007 Ciclosporing 4 times at day NOVA22007 Ciclosporin/Placebo twice daily Placebo
    Number of subjects analysed
    56
    54
    58
    Units: Number of courses
        Month1, zero course
    51
    41
    44
        Month 1, one course
    3
    7
    11
        Month1, two courses
    0
    2
    2
        Month2, zero course
    45
    43
    38
        Month 2, one course
    6
    2
    11
        Month 2, two courses
    2
    2
    3
        Month3, zero course
    43
    42
    34
        Month3, one course
    7
    2
    12
        Month 3, two courses
    1
    2
    4
        Month4, zero course
    42
    41
    38
        Month4, one course
    6
    2
    8
        Month 4, two courses
    2
    1
    2
        Month 4/Early Termination, zero course
    46
    46
    43
        Month 4/Early Termination, one course
    7
    5
    11
        Month 4/Early Termination, two course
    3
    3
    4
    No statistical analyses for this end point

    Secondary: Best Corrected Distance Visual Acuity (BCDVA) in 4-month Randomized Period I

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    End point title
    		 Best Corrected Distance Visual Acuity (BCDVA) in 4-month Randomized Period I
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Month 4/Early Termination
    End point values
    		 LogMAR - High Dose Regimen LogMAR - Low Dose Regimen LogMAR-Placebo Change From Baseline in LogMARHigh Dose Change From Baseline in LogMARLow Dose Change From Baseline in LogMARPlacebo
    Number of subjects analysed
    57
    54
    58
    57
    54
    58
    Units: Letters
    arithmetic mean (standard deviation)
        Baseline
    0.293 ± 0.297
    0.209 ± 0.284
    0.302 ± 0.347
    0 ± 0
    0 ± 0
    0 ± 0
        Month 1
    0.263 ± 0.292
    0.160 ± 0.241
    0.285 ± 0.362
    -0.036 ± 0.187
    -0.058 ± 0.199
    -0.027 ± 0.182
        Month 2
    0.221 ± 0.251
    0.146 ± 0.214
    0.331 ± 0.352
    -0.071 ± 0.191
    -0.073 ± 0.202
    0.003 ± 0.233
        Month 3
    0.172 ± 0.235
    0.110 ± 0.204
    0.273 ± 0.318
    -0.110 ± 0.173
    -0.089 ± 0.233
    -0.066 ± 0.229
        Month 4
    0.149 ± 0.244
    0.097 ± 0.203
    0.237 ± 0.308
    -0.127 ± 0.165
    -0.110 ± 0.233
    -0.109 ± 0.211
        Month 4/Early Termination
    0.158 ± 0.249
    0.114 ± 0.212
    0.217 ± 0.295
    -0.135 ± 0.220
    -0.091 ± 0.257
    -0.097 ± 0.210
    No statistical analyses for this end point

    Secondary: Best Corrected Distance Visual Acuity (BCDVA) in 4-month Randomized Period II

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    End point title
    		 Best Corrected Distance Visual Acuity (BCDVA) in 4-month Randomized Period II
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Month 12/Early Termination
    End point values
    		 LogMAR - High Dose Regimen LogMAR - Low Dose Regimen LogMAR-Placebo Change From Baseline in LogMARHigh Dose Change From Baseline in LogMARLow Dose Change From Baseline in LogMARPlacebo
    Number of subjects analysed
    50
    22
    72
    50
    22
    72
    Units: Letters
    arithmetic mean (standard deviation)
        Baseline (Month 4)
    0.152 ± 0.246
    0.250 ± 0.317
    0.181 ± 0.270
    0 ± 0
    0 ± 0
    0 ± 0
        Month 6
    0.128 ± 0.230
    0.258 ± 0.359
    0.168 ± 0.280
    -0.024 ± 0.114
    -0.017 ± 0.143
    -0.022 ± 0.122
        Month 8
    0.141 ± 0.228
    0.222 ± 0.324
    0.165 ± 0.261
    -0.015 ± 0.136
    -0.029 ± 0.155
    -0.019 ± 0.141
        Month 10
    0.141 ± 0.222
    0.207 ± 0.325
    0.160 ± 0.257
    -0.014 ± 0.149
    -0.044 ± 0.128
    -0.023 ± 0.143
        Month 12
    0.134 ± 0.214
    0.220 ± 0.363
    0.160 ± 0.268
    -0.020 ± 0.152
    -0.030 ± 0.172
    -0.023 ± 0.157
        Month 12/Early Termination
    0.136 ± 0.212
    0.220 ± 0.363
    0.161 ± 0.266
    -0.016 ± 0.154
    -0.030 ± 0.172
    -0.020 ± 0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time the informed consent form was signed until the last study visit at Month 12.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    1) High Dose in period I plus High Dose in period II
    Reporting group description
    		 .1% QID (4 Months) Plus .1% QID (8 Months Safety Follow-up) Participants in this group received High dose in Period I (4 months) and continuing in High dose in the follow up period (8 months).

    Reporting group title
    2) Vehicle in period I plus High Dose in period II
    Reporting group description
    		 Vehicle QID (4 Months) Plus .1% QID (8 Months Safety Follow-up) Participants in this group received Placebo in Period I (4 months) and continuing in High dose in the follow up period (8 months).

    Reporting group title
    3) Total High Dose
    Reporting group description
    		 Total of participants that received High dose from the overall study period (0-12 months).

    Reporting group title
    4) Low Dose in period I plus Low Dose in period II
    Reporting group description
    		 .1% BID + Vehicle BID (4 Months) Plus .1% BID+ Vehicle BID (8 Months Safety Follow-up) Participants in this group received Low dose in Period I (4 months) and continuing in Low dose in the follow up period (8 months).

    Reporting group title
    5) Vehicle in period I plus Low Dose in period II
    Reporting group description
    		 Vehicle QID (4 Months) Plus .1% BID+ Vehicle BID (8 Months Safety Follow-up) Participants in this group received Placebo in Period I (4 months) and continuing in Low dose in the follow up period (8 months).

    Reporting group title
    6) Total Low Dose
    Reporting group description
    		 Total of participants that received Low dose from the overall study period (0-12 months).

    Serious adverse events
    		 1) High Dose in period I plus High Dose in period II 2) Vehicle in period I plus High Dose in period II 3) Total High Dose 4) Low Dose in period I plus Low Dose in period II 5) Vehicle in period I plus Low Dose in period II 6) Total Low Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 22 (0.00%)
    3 / 72 (4.17%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Ulcerative keratitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 1) High Dose in period I plus High Dose in period II 2) Vehicle in period I plus High Dose in period II 3) Total High Dose 4) Low Dose in period I plus Low Dose in period II 5) Vehicle in period I plus Low Dose in period II 6) Total Low Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 50 (58.00%)
    13 / 22 (59.09%)
    42 / 72 (58.33%)
    24 / 44 (54.55%)
    11 / 26 (42.31%)
    35 / 70 (50.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Surgical and medical procedures
    Removal of internal fixation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Application site discharge
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 22 (4.55%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    Application site erosion
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Application site swelling
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Instillation site erythema
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 22 (9.09%)
    3 / 72 (4.17%)
    2 / 44 (4.55%)
    0 / 26 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    1
    5
    6
    2
    0
    2
    Instillation site foreign body sensation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Instillation site lacrimation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Instillation site pain
         subjects affected / exposed
    6 / 50 (12.00%)
    4 / 22 (18.18%)
    10 / 72 (13.89%)
    5 / 44 (11.36%)
    0 / 26 (0.00%)
    5 / 70 (7.14%)
         occurrences all number
    7
    5
    12
    10
    0
    10
    Instillation site pruritus
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 22 (13.64%)
    5 / 72 (6.94%)
    4 / 44 (9.09%)
    0 / 26 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    2
    6
    8
    4
    0
    4
    Pyrexia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    2 / 44 (4.55%)
    1 / 26 (3.85%)
    3 / 70 (4.29%)
         occurrences all number
    1
    0
    1
    2
    1
    3
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Allergic respiratory disease
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Asthma
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    1 / 26 (3.85%)
    2 / 70 (2.86%)
         occurrences all number
    0
    0
    0
    2
    1
    3
    Cough
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 22 (4.55%)
    4 / 72 (5.56%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    3
    1
    4
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    1 / 44 (2.27%)
    1 / 26 (3.85%)
    2 / 70 (2.86%)
         occurrences all number
    2
    0
    2
    1
    1
    2
    Rhinitis allergic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Sneezing
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 22 (4.55%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Intraocular pressure decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    Intraocular pressure increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Protein total increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 22 (4.55%)
    5 / 72 (6.94%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    6
    1
    7
    0
    1
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 22 (4.55%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Eye disorders
    Abnormal sensation in eye
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Blepharitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Cataract subcapsular
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 22 (4.55%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Conjunctival irritation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Corneal deposits
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 22 (4.55%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Corneal leukoma
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 22 (0.00%)
    2 / 72 (2.78%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    3
    0
    3
    0
    3
    3
    Corneal neovascularisation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Diplopia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Erythema of eyelid
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Eye irritation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    1 / 26 (3.85%)
    2 / 70 (2.86%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    Eye pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Eye pruritus
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 22 (13.64%)
    3 / 72 (4.17%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    3
    3
    0
    1
    1
    Eyelid erosion
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 22 (4.55%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Eyelid ptosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Foreign body sensation in eyes
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    Lacrimation increased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Meibomianitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Ocular discomfort
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 22 (9.09%)
    2 / 72 (2.78%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 22 (9.09%)
    4 / 72 (5.56%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    4
    2
    6
    0
    1
    1
    Pharyngitis
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 22 (0.00%)
    2 / 72 (2.78%)
    0 / 44 (0.00%)
    2 / 26 (7.69%)
    2 / 70 (2.86%)
         occurrences all number
    2
    0
    2
    0
    5
    5
    Ulcerative keratitis
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 22 (0.00%)
    2 / 72 (2.78%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    3
    0
    3
    1
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Aphthous stomatitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    1
    0
    1
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    Nausea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Oral pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Dermatitis allergic
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 22 (4.55%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    3
    3
    0
    0
    0
    Dermatitis atopic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Eczema
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    Papule
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    1 / 44 (2.27%)
    1 / 26 (3.85%)
    2 / 70 (2.86%)
         occurrences all number
    1
    0
    1
    1
    1
    2
    Rash generalised
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Growing pains
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 22 (4.55%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    4
    4
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    1 / 26 (3.85%)
    0 / 70 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Conjunctivitis viral
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Eye infection bacterial
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Folliculitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Hordeolum
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Influenza
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 22 (0.00%)
    4 / 72 (5.56%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    4
    0
    4
    0
    0
    0
    Laryngitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    Molluscum contagiosum
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 22 (4.55%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 22 (0.00%)
    3 / 72 (4.17%)
    5 / 44 (11.36%)
    1 / 26 (3.85%)
    6 / 70 (8.57%)
         occurrences all number
    6
    0
    6
    6
    2
    8
    Otitis externa
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Parasitic gastroenteritis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    1
    0
    1
    0
    2
    2
    Sinusitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    0 / 44 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Tonsillitis
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 22 (0.00%)
    2 / 72 (2.78%)
    2 / 44 (4.55%)
    0 / 26 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    2
    0
    2
    2
    0
    2
    Tooth abscess
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 22 (0.00%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 22 (0.00%)
    2 / 72 (2.78%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    Varicella
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 22 (4.55%)
    1 / 72 (1.39%)
    0 / 44 (0.00%)
    0 / 26 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 22 (0.00%)
    0 / 72 (0.00%)
    1 / 44 (2.27%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2013
    This amendment addressed the following changes based on the change requests after the single application: • Adding exclusion criterion 4: “History of ocular varicella-zoster or vaccinia virus infection.” • Adding the procedure that patients receiving rescue medication are needed to have the IOP measured at each study visit. • Adding an explanation on the method to reduce systemic absorption of rescue therapy by nasolacrimal occlusion using compression of lacrimal ducts. • Adding of the QUICK questionnaire for the assessment of QoL.
    02 Jan 2014
    This amendment was country specific for Croatia .Modification of inclusion criterion 3 to match country specific requirements (related to contraception).

    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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