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    Clinical Trial Results:
    An 8-week phase I/II, multicenter, randomized, double-masked, vehicle controlled parallel group study with a 48 or 56 week open-label follow-up period to evaluate the safety and efficacy of two doses (10 µg/ml and 20 µg/ml) of recombinant human nerve growth factor eye drops solution versus vehicle in patients with Stage 2 and 3 of Neurotrophic Keratitis.

    Summary
    EudraCT number
    		 2012-002527-15
    Trial protocol
    		 GB   DE   PT   HU   ES   PL   BE  
    Global end of trial date
    19 May 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Aug 2021
    First version publication date
    04 Jun 2017
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    XML v8 format of the data need to be generated

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NGF0212
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dompé Farmaceutici s.p.a.
    Sponsor organisation address
    via santa Lucia 6, Milano, Italy, 20122
    Public contact
    Project Development Direction, Dompé Farmaceutici s.p.a., 0039 0258383500, info@dompe.it
    Scientific contact
    Project Development Direction, Dompé Farmaceutici s.p.a., 0039 0258383500, info@dompe.it
    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
    19 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    19 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the safety and the efficacy of 2 dose regimens (10 μg/ml or 20 μg/ml 6 times a day) of recombinant human Nerve Growth Factor (rhNGF) eye drops solution compared to vehicle for inducing a complete healing of Stage 2 persistent epithelial defect (PED) and Stage 3 (corneal ulcer) neurotrophic keratitis (NK) as measured by the central reading center evaluating the clinical pictures of corneal fluorescein staining.
    Protection of trial subjects
    The clinical study protocol, protocol amendments, informed consent document(s), and any other appropriate study-related documents were reviewed and approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB). This study was conducted in accordance with the accepted version of the Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of the Code of Federal Regulations, and in compliance with Good Clinical Practice (GCP) guidelines. Informed consent was obtained prior to the conduct of any study-related procedures. The Investigator ensured that all personnel involved in the conduct of the study were qualified to perform their assigned responsibilities through education, training and experience. Any deviations from GCP are described in the report. The consent document met all applicable local laws and provided the patient with information regarding the purpose, procedures, requirements and restrictions of the study, along with any known risks and potential benefits associated with the investigational product and the established provisions for maintaining the confidentiality of personal information.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jan 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
    Poland: 7
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Germany: 40
    Country: Number of subjects enrolled
    Italy: 87
    Country: Number of subjects enrolled
    France: 11
    Worldwide total number of subjects
    174
    EEA total number of subjects
    174
    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)
    97
    From 65 to 84 years
    68
    85 years and over
    9

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study consisted of 2periods:an 8week PhaseI/IIcontrolled treatment period and 48/56-week FU period.In the Phase1 patients were randomized into 2cohorts (of9patients each). In phase2patients were randomized in a 1:1:1ratio(52patients each group).Data refer to the 1st database lock when the last patient in Phase2 had completed12weeks of FU period

    Pre-assignment
    Screening details
    		 The inclusion/exclusion criteria were designed to include individuals 18 years of age or older with Stage 2 (PED) or Stage 3 (corneal ulcer) NK involving only 1 eye and to exclude those with Stage 2 or 3 NK affecting both eyes, any active ocular infection or inflammation not related to NK, or any ocular disease or severe vision loss.

    Period 1
    Period 1 title
    Treatment period: Phase I/II
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Subject
    Blinding implementation details
    During the 8-week randomized, double-masked controlled treatment period, the patient, the Investigator, all other site staff involved in study , and the Sponsor’s clinical personnel were blinded to the study treatment. The vials of rhNGF (both doses) and the ones containing the vehicle of rhNGF were identical in appearance and the contents of the vials were indistinguishable.The kit numbers were generated by a SAS programming group.Each kit number was randomly associated with a treatment group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1_rhNGF10_Phase 1_treatment
    Arm description
    		 cohort1: active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF).
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhNGF 10 μg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    rhNGF 10 μg/ml : one drop 6 times a day (one 35 μl drop equals to 0.35 μg of rhNGF) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Arm title
    		 2_rhNGF20_Phase 1_treatment
    Arm description
    		 cohort 2: active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhNGF 20 μg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Arm title
    		 3_vehicle group_Phase 1_treatment
    Arm description
    		 cohort 1 and 2: vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period
    Arm type
    		 Placebo

    Investigational medicinal product name
    ophthalmic solution of the same composition as the test product without rhNGF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    one drop 6 times a day (35 μl each drop ) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Arm title
    		 4_rhNGF10_Phase 2_treatment
    Arm description
    		 active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF)
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhNGF 10 μg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    rhNGF 10 μg/ml : one drop 6 times a day (one 35 μl drop equals to 0.35 μg of rhNGF) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Arm title
    		 5_rhNGF20_Phase 2_treatment
    Arm description
    		 active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhNGF 20 μg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Arm title
    		 6_vehicle group_Phase 2_treatment
    Arm description
    		 vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period
    Arm type
    		 Placebo

    Investigational medicinal product name
    ophthalmic solution of the same composition as the test product without rhNGF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    one drop 6 times a day (35 μl each drop ) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Number of subjects in period 1
    		1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Started
    7
    7
    4
    52
    52
    52
    Completed
    6
    6
    2
    45
    39
    48
    Not completed
    1
    1
    2
    7
    13
    4
         Adverse event, serious fatal
    -
    -
    -
    -
    1
    -
         withdrawal of consent
    -
    1
    -
    -
    -
    -
         Adverse event, non-fatal
    1
    -
    2
    3
    8
    1
         other
    -
    -
    -
    1
    2
    2
         decision unrelated to adverse event
    -
    -
    -
    1
    1
    1
         Lack of efficacy
    -
    -
    -
    2
    1
    -
    Period 2
    Period 2 title
    Follow Up period Phase I/II
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Subject
    Blinding implementation details
    During the uncontrolled period, the patient, the Investigator, all other site staff involved in study , and the Sponsor’s clinical personnel were blinded to the study treatment. The vials of rhNGF (both doses) and the ones containing the vehicle of rhNGF were identical in appearance and the contents of the vials were indistinguishable.The kit numbers were generated by a SAS programming group.Each kit number was randomly associated with a treatment group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1_rhNGF10_Phase 1_FU
    Arm description
    		 cohort1: active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF).
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhNGF 10 μg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    rhNGF 10 μg/ml : one drop 6 times a day (one 35 μl drop equals to 0.35 μg of rhNGF) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Arm title
    		 2_rhNGF20_Phase 1_FU
    Arm description
    		 cohort 2: active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhNGF 20 μg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Arm title
    		 3_vehicle group_Phase 1_FU
    Arm description
    		 cohort 1 and 2: vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period
    Arm type
    		 Placebo

    Investigational medicinal product name
    ophthalmic solution of the same composition as the test product without rhNGF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    one drop 6 times a day (35 μl each drop ) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Arm title
    		 4_rhNGF10_Phase 2_FU
    Arm description
    		 active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF)
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhNGF 10 μg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    rhNGF 10 μg/ml : one drop 6 times a day (one 35 μl drop equals to 0.35 μg of rhNGF) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Arm title
    		 5_rhNGF20_Phase 2_FU
    Arm description
    		 active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhNGF 20 μg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    one drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Arm title
    		 6_vehicle group_Phase 2_FU
    Arm description
    		 vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period
    Arm type
    		 Placebo

    Investigational medicinal product name
    ophthalmic solution of the same composition as the test product without rhNGF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    one drop 6 times a day (35 μl each drop ) according to this scheme: morning (8 AM) Mid-morning (10 AM) Noon (12 PM) Early afternoon (2 PM) Mid afternoon (4 PM) Late afternoon (6 PM)

    Number of subjects in period 2
    		1_rhNGF10_Phase 1_FU 2_rhNGF20_Phase 1_FU 3_vehicle group_Phase 1_FU 4_rhNGF10_Phase 2_FU 5_rhNGF20_Phase 2_FU 6_vehicle group_Phase 2_FU
    Started
    6
    6
    2
    45
    39
    48
    Completed
    5
    5
    1
    12
    13
    15
    Not completed
    1
    1
    1
    33
    26
    33
         Adverse event, serious fatal
    -
    -
    -
    5
    -
    1
         Adverse event, non-fatal
    1
    -
    -
    -
    -
    -
         still in study after week 20
    -
    -
    -
    25
    23
    25
         other
    -
    -
    -
    1
    3
    5
         Lost to follow-up
    -
    -
    1
    2
    -
    1
         parent withdrew the consent to continue the follow
    -
    1
    -
    -
    -
    -
         Lack of efficacy
    -
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1_rhNGF10_Phase 1_treatment
    Reporting group description
    		 cohort1: active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF).

    Reporting group title
    2_rhNGF20_Phase 1_treatment
    Reporting group description
    		 cohort 2: active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

    Reporting group title
    3_vehicle group_Phase 1_treatment
    Reporting group description
    		 cohort 1 and 2: vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period

    Reporting group title
    4_rhNGF10_Phase 2_treatment
    Reporting group description
    		 active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF)

    Reporting group title
    5_rhNGF20_Phase 2_treatment
    Reporting group description
    		 active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

    Reporting group title
    6_vehicle group_Phase 2_treatment
    Reporting group description
    		 vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period

    Reporting group values
    		 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment Total
    Number of subjects
    		 7 7 4 52 52 52 174
    Age categorical
    age categorical characteristics are overall described in the trial information section.
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.7 ± 21.47 52 ± 17.24 64.3 ± 24.06 59 ± 17.17 62.5 ± 14.01 60.4 ± 16.78 -
    Gender categorical
    Units: Subjects
        Female
    		 3 4 2 30 30 35 104
        Male
    		 4 3 2 22 22 17 70
    ethnicity
    ethnicity characteristics
    Units: Subjects
        hispanic, latino or spanish
    		 1 0 0 6 9 5 21
        not hispanic, latino or spanish
    		 6 6 4 42 42 41 141
        NA
    		 0 1 0 4 1 6 12
    race
    race characteristics
    Units: Subjects
        NA
    		 0 1 0 5 1 5 12
        white
    		 7 6 4 46 51 45 159
        black or african
    		 0 0 0 0 0 1 1
        asian
    		 0 0 0 1 0 1 2

    End points

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    End points reporting groups
    Reporting group title
    1_rhNGF10_Phase 1_treatment
    Reporting group description
    		 cohort1: active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF).

    Reporting group title
    2_rhNGF20_Phase 1_treatment
    Reporting group description
    		 cohort 2: active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

    Reporting group title
    3_vehicle group_Phase 1_treatment
    Reporting group description
    		 cohort 1 and 2: vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period

    Reporting group title
    4_rhNGF10_Phase 2_treatment
    Reporting group description
    		 active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF)

    Reporting group title
    5_rhNGF20_Phase 2_treatment
    Reporting group description
    		 active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

    Reporting group title
    6_vehicle group_Phase 2_treatment
    Reporting group description
    		 vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period
    Reporting group title
    1_rhNGF10_Phase 1_FU
    Reporting group description
    		 cohort1: active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF).

    Reporting group title
    2_rhNGF20_Phase 1_FU
    Reporting group description
    		 cohort 2: active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

    Reporting group title
    3_vehicle group_Phase 1_FU
    Reporting group description
    		 cohort 1 and 2: vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period

    Reporting group title
    4_rhNGF10_Phase 2_FU
    Reporting group description
    		 active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF)

    Reporting group title
    5_rhNGF20_Phase 2_FU
    Reporting group description
    		 active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

    Reporting group title
    6_vehicle group_Phase 2_FU
    Reporting group description
    		 vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period

    Primary: percentage of patient experiencing complete healing at week 4 by central reading

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    End point title
    		 percentage of patient experiencing complete healing at week 4 by central reading [1]
    End point description
    The primary efficacy variable was defined as complete healing of the PED or corneal ulcer measured using corneal fluorescein staining by the central reading center evaluating the clinical pictures. The primary efficacy endpoint was the percentage of patients experiencing complete healing, defined as the greatest diameter of the corneal fluorescein staining in the area of the PED or corneal ulcer, as determined by the reading center, being less than 0.5 mm at the Week 4 visit. An observed case analysis for complete healing at Week 4 was also conducted.
    End point type
    Primary
    End point timeframe
    evaluation is about the complete healing at week 4 visit,
    Notes
    [1] - 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: This endpoint is evaluated only for the selected group: all the available results have been reported.
    End point values
    		 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Number of subjects analysed
    52
    52
    52
    Units: percentage
        yes
    55
    58
    20
        no
    45
    42
    80
    Statistical analysis title
    		 Complete Healing at Week 4_rhNGF10 vs veich
    Statistical analysis description
    Primary Efficacy Analysis of Percentage of Patients who Achieved Complete Healing at Week 4 (LOCF) as Determined by the Reading Center. Comparison between rhNGF10 and veichle
    Comparison groups
    4_rhNGF10_Phase 2_treatment v 6_vehicle group_Phase 2_treatment
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 difference in percentage
    Point estimate
    35.3
    Confidence interval
         level
    		 97.06%
         sides
    2-sided
         lower limit
    		 15.88
         upper limit
    		 54.71
    Statistical analysis title
    		 Complete Healing at Week 4_rhNGF20 vs veich
    Comparison groups
    5_rhNGF20_Phase 2_treatment v 6_vehicle group_Phase 2_treatment
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Parameter type
    		 difference in percentage
    Point estimate
    38.4
    Confidence interval
         level
    		 97.06%
         sides
    2-sided
         lower limit
    		 18.96
         upper limit
    		 57.83

    Primary: Adverse events

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    End point title
    		 Adverse events [2]
    End point description
    AEs, SAEs and ADRs were collected throughout the study .Results for specific adverse event categories are reported in the "adverse event" section. Results report the percentage of patients that reported an Adverse event (both serious and not) during the considered period (week 8 and week 20): percentage of patients reported in the FU period (period 2) take into account also the percentage of patient results from treatment period (period 1). Whole Adverse events ( also AEs after 12 weeks Follow Up, described in the CSR Addendum Report) are attached. No relapses are occurred during the FU period: in any case all the AE tables are attached.
    End point type
    Primary
    End point timeframe
    period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, untill week 20)
    Notes
    [2] - 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: Available results were reported, but no statistical analyses have been done.
    End point values
    		 1_rhNGF10_Phase 1_treatment 1_rhNGF10_Phase 1_FU 2_rhNGF20_Phase 1_treatment 2_rhNGF20_Phase 1_FU 3_vehicle group_Phase 1_treatment 3_vehicle group_Phase 1_FU 4_rhNGF10_Phase 2_treatment 4_rhNGF10_Phase 2_FU 5_rhNGF20_Phase 2_treatment 5_rhNGF20_Phase 2_FU 6_vehicle group_Phase 2_treatment 6_vehicle group_Phase 2_FU
    Number of subjects analysed
    7
    6
    7
    6
    4
    2
    52
    45
    52
    39
    52
    48
    Units: 0-100%
    43
    57
    71
    29
    100
    50
    44
    36
    52
    26
    39
    31
    Attachments
    		 Untitled (Filename: 16.2.7.1.a Adverse Events_Phase 1.pdf)
    16.2.7.1.b Adverse Events_Phase 2
    Untitled (Filename: 14.3.1.1.a Adverse Events Overall_Phase 1.pdf)
    Untitled (Filename: 14.3.1.1.b Adverse Events Overall_Phase 2.pdf)
    Untitled (Filename: 14.3.1.2.a Adverse Events per SOC_Phase 1.pdf)
    Untitled (Filename: 14.3.1.2.b Adverse Events per SOC_Phase 2.pdf)
    Untitled (Filename: 14.3.1.5.a Adverse Events treatment related_Phase 1.pdf)
    Untitled (Filename: 14.3.1.5.b Adverse Events treatment related_Phase 2.pdf)
    Untitled (Filename: 14.3.1.6.a Serious Adverse Events_Phase 1.pdf)
    Untitled (Filename: 14.3.1.6.b Serious Adverse Events_Phase 1.pdf)
    Untitled (Filename: 14.3.2.3.a Adverse Events leading to death_Phase 1.pdf)
    Untitled (Filename: 14.3.2.3.b Adverse Events leading to death_Phase 2.pdf)
    Untitled (Filename: 14.3.1.1c Summary of AE _CSR Addendun.pdf)
    Untitled (Filename: 14.3.1.2c Summary of AE by SOC _CSR Addendun.pdf)
    Untitled (Filename: 14.3.1.5c Summary of Treatment Related AE _CSR Addendun.pdf)
    Untitled (Filename: 14.3.1.6c Serious Adverse Events _CSR Addendun.pdf)
    Untitled (Filename: 14.3.2.3c Adverse Events Leading to death _CSR Addendun.pdf)
    Untitled (Filename: 16.2.7.1c AE.pdf)
    No statistical analyses for this end point

    Secondary: Percentage of patients experiencing complete healing at week 4 by investigator

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    End point title
    		 Percentage of patients experiencing complete healing at week 4 by investigator [3]
    End point description
    Percentage of patients experiencing complete healing of the PED or corneal ulcer determined by corneal fluorescein staining at 4 weeks as defined by the Investigator
    End point type
    Secondary
    End point timeframe
    analysis conducted at 4 weeks
    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: This endpoint is evaluated only for the selected group : all the available results have been reported.
    End point values
    		 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Number of subjects analysed
    52
    52
    52
    Units: percentage
        yes
    52
    61
    26
        no
    48
    39
    74
    Statistical analysis title
    		 Complete Healing at Week 4_rhNGF10 vs veich
    Statistical analysis description
    by investigators judjment
    Comparison groups
    4_rhNGF10_Phase 2_treatment v 6_vehicle group_Phase 2_treatment
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.016
    Method
    		 Chi-squared
    Parameter type
    		 difference in percentage
    Point estimate
    25.8
    Confidence interval
         level
    		 97.06%
         sides
    2-sided
         lower limit
    		 3.66
         upper limit
    		 47.87
    Statistical analysis title
    		 Complete Healing at Week 4_rhNGF20 vs veich
    Statistical analysis description
    according to investigator's judjment
    Comparison groups
    5_rhNGF20_Phase 2_treatment v 6_vehicle group_Phase 2_treatment
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.002
    Method
    		 Chi-squared
    Parameter type
    		 difference in percentage
    Point estimate
    34.7
    Confidence interval
         level
    		 97.06%
         sides
    2-sided
         lower limit
    		 11.91
         upper limit
    		 57.41

    Secondary: Percentage of patients experiencing complete healing at week 8 by central reading and investigator

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    End point title
    		 Percentage of patients experiencing complete healing at week 8 by central reading and investigator [4]
    End point description
    percentage of patients who achieved complete healing of the PED or corneal ulcer at 8 weeks as measured by central reading and investigator.
    End point type
    Secondary
    End point timeframe
    anlysis conducted at 8 weeks
    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: This endpoint is evaluated only for the selected group : all the available results have been reported.
    End point values
    		 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Number of subjects analysed
    52
    52
    52
    Units: percentage
        central reading_yes
    78
    83
    56
        central reading_no
    22
    17
    44
        investigator_yes
    79
    79
    53
        investigator_no
    21
    21
    47
    Statistical analysis title
    		 Complete Healing Week 8_rhNGF10vs veich_Central
    Comparison groups
    4_rhNGF10_Phase 2_treatment v 6_vehicle group_Phase 2_treatment
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.031
    Method
    		 Chi-squared
    Parameter type
    		 difference in percentage
    Point estimate
    21.9
    Confidence interval
         level
    		 97.06%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 43.64
    Statistical analysis title
    		 Complete Healing Week 8_rhNGF20vs veich_Central
    Comparison groups
    5_rhNGF20_Phase 2_treatment v 6_vehicle group_Phase 2_treatment
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.008
    Method
    		 Chi-squared
    Parameter type
    		 difference in percentage
    Point estimate
    26.9
    Confidence interval
         level
    		 97.06%
         sides
    2-sided
         lower limit
    		 5.57
         upper limit
    		 48.28
    Statistical analysis title
    		 Complete Healing Week 8_rhNGF10vs veich_Investigat
    Statistical analysis description
    according to investigator's judjment
    Comparison groups
    4_rhNGF10_Phase 2_treatment v 6_vehicle group_Phase 2_treatment
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.011
    Method
    		 Chi-squared
    Parameter type
    		 difference in percentage
    Point estimate
    26.1
    Confidence interval
         level
    		 97.06%
         sides
    2-sided
         lower limit
    		 4.18
         upper limit
    		 48.01
    Statistical analysis title
    		 Complete Healing Week 8_rhNGF20vs veich_Investigat
    Statistical analysis description
    according to investigator's judjment
    Comparison groups
    5_rhNGF20_Phase 2_treatment v 6_vehicle group_Phase 2_treatment
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.014
    Method
    		 Chi-squared
    Parameter type
    		 difference in percentage
    Point estimate
    25.9
    Confidence interval
         level
    		 97.06%
         sides
    2-sided
         lower limit
    		 3.55
         upper limit
    		 48.33

    Secondary: Visual Analogue Scale (VAS) for ocular tolerability

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    End point title
    		 Visual Analogue Scale (VAS) for ocular tolerability
    End point description
    Ocular tolerability was recorded by the patient on a VAS scale from 0 to 100 mm, where a higher VAS score indicates worse ocular symptoms (0 means no symptoms and 100 means the worst possible discomfort). The overall VAS score for ocular tolerability was calculated as the mean of the individual VAS scores for the 7 different symptoms (foreign body sensation, burning/stinging, itching, ocular pain, sticky feeling, blurred vision and photophobia). A summary of ocular tolerability as measured by the VAS for the Safety population is provided. Overall ocular tolerability VAS scores decreased from Baseline to Week 8 in the rhNGF treatment groups and the vehicle control group, indicating an improvement in ocular tolerability. Result are below reported as per symptoms at week 8 (for treatment period) and week 20 (for Follow Up period). Results described in the CSR Addendum Report are attached.
    End point type
    Secondary
    End point timeframe
    period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, untill week 20)
    End point values
    		 1_rhNGF10_Phase 1_treatment 1_rhNGF10_Phase 1_FU 2_rhNGF20_Phase 1_treatment 2_rhNGF20_Phase 1_FU 3_vehicle group_Phase 1_treatment 3_vehicle group_Phase 1_FU 4_rhNGF10_Phase 2_treatment 4_rhNGF10_Phase 2_FU 5_rhNGF20_Phase 2_treatment 5_rhNGF20_Phase 2_FU 6_vehicle group_Phase 2_treatment 6_vehicle group_Phase 2_FU
    Number of subjects analysed
    7
    6
    7
    6
    4
    2
    52
    45
    52
    39
    52
    48
    Units: VAS Scale
    arithmetic mean (standard deviation)
        Foreign Body Sensation_Baseline
    50.4 ± 25.68
    50.4 ± 25.68
    24 ± 19.76
    24 ± 19.76
    20.5 ± 29.23
    20.5 ± 29.23
    34.8 ± 29.4
    34.8 ± 29.4
    35.4 ± 34.79
    35.4 ± 34.79
    37.7 ± 36.49
    37.7 ± 36.49
        Foreign Body Sensation_CFB
    -21.2 ± 25.96
    -20 ± 30.32
    -12.9 ± 17.03
    -13 ± 25.3
    -16 ± 65.05
    -52 ± 0
    -8.8 ± 34.68
    -16.6 ± 31.26
    -16.5 ± 36.87
    -22.4 ± 38.77
    -20.9 ± 35.86
    -20.7 ± 30.57
        burning/stinging_baseline
    41.4 ± 30.85
    41.4 ± 30.85
    30.7 ± 38.78
    30.7 ± 38.78
    18 ± 28.57
    18 ± 28.57
    32.5 ± 32.88
    32.5 ± 32.88
    26.5 ± 30.86
    26.5 ± 30.86
    30.2 ± 32.21
    30.2 ± 32.21
        burning/stinging_CFB
    -14.7 ± 38.02
    -18 ± 41.65
    -12.1 ± 28.27
    -16.5 ± 17.13
    -28.5 ± 23.33
    -12 ± 0
    -3.8 ± 42.13
    -14.9 ± 40.35
    -2.5 ± 26.76
    -10.8 ± 31.51
    -18 ± 32.97
    -14.7 ± 37.54
        itching_baseline
    17 ± 27.4
    17 ± 27.4
    18.7 ± 19.62
    18.7 ± 19.62
    7.8 ± 15.5
    7.8 ± 15.5
    24.1 ± 27.48
    24.1 ± 27.48
    21.8 ± 28.68
    21.8 ± 28.68
    22.9 ± 28.43
    22.9 ± 28.43
        itching_CFB
    -3 ± 17.93
    -7.8 ± 27.18
    -10 ± 23.1
    -4.2 ± 28.51
    -15.5 ± 21.92
    -31 ± 0
    -10.8 ± 29.25
    -10.2 ± 30.62
    -7.3 ± 22.67
    -11.9 ± 23.05
    -8.9 ± 25.59
    -4.8 ± 30.71
        ocular pain_baseline
    34.1 ± 36.96
    34.1 ± 36.96
    33.6 ± 34.73
    33.6 ± 34.73
    19 ± 38
    19 ± 38
    32.8 ± 34.86
    32.8 ± 34.86
    21.1 ± 28.38
    21.1 ± 28.38
    28.8 ± 32.82
    28.8 ± 32.82
        ocular pain_CFB
    -21.2 ± 28.96
    -16 ± 28.59
    -6 ± 30.72
    -9.3 ± 11.86
    -23 ± 32.53
    -26 ± 0
    -2 ± 43
    -16.7 ± 34.66
    2 ± 37.25
    -12.1 ± 31.25
    -16.3 ± 30.52
    -18.3 ± 34.3
        sticky feeling_baseline
    47.6 ± 34.14
    47.6 ± 34.14
    32.1 ± 35.34
    32.1 ± 35.34
    15.5 ± 23.69
    15.5 ± 23.69
    26.6 ± 29.65
    26.6 ± 29.65
    17.4 ± 22.07
    17.4 ± 22.07
    26.1 ± 31.93
    26.1 ± 31.93
        sticky feeling_CFB
    -7.2 ± 42.82
    -19.8 ± 22.18
    -18.7 ± 38.32
    -0.7 ± 12.52
    -11 ± 5.66
    -2 ± 0
    -11.7 ± 30.17
    -13.3 ± 30.75
    -4.3 ± 29.55
    -11.4 ± 31.11
    -10.7 ± 29.95
    -8.3 ± 30.62
        blurred vision_baseline
    71 ± 38.37
    71 ± 38.37
    85.7 ± 14.74
    85.7 ± 14.74
    93.5 ± 7.9
    93.5 ± 7.9
    80.2 ± 25.18
    80.2 ± 25.18
    83.2 ± 24.45
    83.2 ± 24.45
    78.5 ± 24.68
    78.5 ± 24.68
        blurred vision_CFB
    -25.7 ± 34.37
    -26.5 ± 31.18
    -25 ± 32.15
    -26.2 ± 17.93
    -22 ± 31.11
    -14 ± 0
    -24.9 ± 35.33
    -16.5 ± 38.43
    -26.2 ± 31.58
    -25.7 ± 34.41
    -17.4 ± 28.55
    -17.4 ± 27.14
        photophobia_baseline
    64.7 ± 42.9
    64.7 ± 42.9
    66.6 ± 29.85
    66.6 ± 29.85
    30.3 ± 26.21
    30.3 ± 26.21
    64.3 ± 32.07
    64.3 ± 32.07
    57.6 ± 36.1
    57.6 ± 36.1
    65.2 ± 34.71
    65.2 ± 34.71
        photophobia_CFB
    -19.5 ± 27.98
    -20.3 ± 28.63
    -20.7 ± 34.13
    -26 ± 39.88
    -30.5 ± 43.13
    -61 ± 0
    -17.8 ± 41.23
    -24.2 ± 37.51
    -13.2 ± 40.44
    -21 ± 38.76
    -17.5 ± 29.02
    -14.6 ± 29.19
    Attachments
    		 Untitled (Filename: 14.3.6.2c VAS.pdf)
    No statistical analyses for this end point

    Secondary: Best Corrected Distance Visual Acuity (BCDVA)

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    End point title
    		 Best Corrected Distance Visual Acuity (BCDVA)
    End point description
    Best-Corrected Distance Visual Acuity (BCDVA) by means of the Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity chart at 4 meters (13 feet).During the treatment period(phase1), an improvement was seen in the mean BCDVA scores in both rhNGF treatment groups, which was not observed in the vehicle group. During the follow-up period, a greater improvement in the mean BCDVA scores was observed in both rhNGF treatment groups (with a higher improvement in the rhNGF 20 μg/ml group). During the controlled treatment period(phase2), a greater improvement in the mean BCDVA score was observed in both rhNGF treatment groups compared to the vehicle group.During the uncontrolled treatment period(phase2)an increase was seen in the mean BCDVA score in the rhNGF 20 μg/ml group.During the follow-up period(phase2)an improvement in the mean BCDVA score was observed in both rhNGF treatment groups and the vehicle.Data reported refers to week n° 8 (treatment group)and n°12/20(FU group)
    End point type
    Secondary
    End point timeframe
    period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, untill week 20). Results described in the CSR Addendum Report are attached.
    End point values
    		 1_rhNGF10_Phase 1_treatment 1_rhNGF10_Phase 1_FU 2_rhNGF20_Phase 1_treatment 2_rhNGF20_Phase 1_FU 3_vehicle group_Phase 1_treatment 3_vehicle group_Phase 1_FU 4_rhNGF10_Phase 2_treatment 4_rhNGF10_Phase 2_FU 5_rhNGF20_Phase 2_treatment 5_rhNGF20_Phase 2_FU 6_vehicle group_Phase 2_treatment 6_vehicle group_Phase 2_FU
    Number of subjects analysed
    7
    6
    7
    6
    4
    2
    52
    45
    52
    39
    52
    48
    Units: Number of ETDRS letters
    arithmetic mean (standard deviation)
        baseline
    42 ± 28.25
    42 ± 28.25
    30.4 ± 24.85
    30.4 ± 24.85
    9.5 ± 11.96
    9.5 ± 11.96
    30.7 ± 28.35
    30.7 ± 28.35
    24.2 ± 25.88
    24.2 ± 25.88
    32.4 ± 26.07
    32.4 ± 26.07
        change from baseline
    9.3 ± 5.89
    11.2 ± 7.47
    8.7 ± 12.41
    7 ± 9.8
    -1 ± 1.41
    -6 ± 0
    15.8 ± 16.82
    13.2 ± 16.8
    11.9 ± 20.9
    14.2 ± 19.06
    6.9 ± 15.44
    8.8 ± 14.27
    Attachments
    		 Untitled (Filename: 14.3.9c BCDVA.pdf)
    No statistical analyses for this end point

    Secondary: Intraocular Pressure (IOP)

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    End point title
    		 Intraocular Pressure (IOP)
    End point description
    IOP was measured using a Goldmann applanation tonometer, a handheld applanation tonometer [eg, Tonopen], or other tonometer, after the instillation of a topical anesthetic. During the follow-up period (phase1), minimal fluctuations in IOP were observed in all 3 treatment groups. Minimal fluctuations in IOP were observed during the uncontrolled treatment period and during the follow-up period (phase2). There were no notable trends or differences between treatment groups. Results described in the CSR Addendum Report are attached.
    End point type
    Secondary
    End point timeframe
    period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, untill week 20)
    End point values
    		 1_rhNGF10_Phase 1_treatment 1_rhNGF10_Phase 1_FU 2_rhNGF20_Phase 1_treatment 2_rhNGF20_Phase 1_FU 3_vehicle group_Phase 1_treatment 3_vehicle group_Phase 1_FU 4_rhNGF10_Phase 2_treatment 4_rhNGF10_Phase 2_FU 5_rhNGF20_Phase 2_treatment 5_rhNGF20_Phase 2_FU 6_vehicle group_Phase 2_treatment 6_vehicle group_Phase 2_FU
    Number of subjects analysed
    7
    6
    7
    6
    4
    2
    52
    45
    52
    39
    52
    48
    Units: mmHg
    arithmetic mean (standard deviation)
        baseline
    16.1 ± 3.85
    16.1 ± 3.85
    11.3 ± 3.68
    11.3 ± 3.68
    11.8 ± 3.3
    11.8 ± 3.3
    14.3 ± 3.16
    14.3 ± 3.16
    14 ± 3.06
    14 ± 3.06
    14.1 ± 3.16
    14.1 ± 3.16
        change from baseline
    -1.8 ± 2.48
    -2.2 ± 2.49
    1.9 ± 5.24
    2.3 ± 3.78
    3.5 ± 2.12
    -3 ± 0
    -0.1 ± 3.71
    0.2 ± 3.25
    0.9 ± 2.61
    0.1 ± 3.64
    0.8 ± 3.43
    0.6 ± 3.93
    Attachments
    		 Untitled (Filename: 14.3.7.1c IOP.pdf)
    No statistical analyses for this end point

    Secondary: Dilated fundus ophthalmoscopy

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    End point title
    		 Dilated fundus ophthalmoscopy
    End point description
    Dilated fundus ophthalmoscopy was performed at specific time points to assess the retina, macula, choroid and optic nerve head after dilation of the pupil. Percentage of patients with each rating is summarized for each eye structure by treatment and visit for the controlled treatment period and follow-up period for Phase I and Phase II separately. Shifts from baseline (from normal to abnormal) results are reported for eye structure (Vitreous, Retina macula, Choroid, Optic nerve) at week 8 (for treatment group). Summary of fundus ophthalmoscophy by treatment and visist is reported in the table attached.
    End point type
    Secondary
    End point timeframe
    period 1 (8 weeks) and 2 (Follow Up period of 12 weeks, untill week 20)
    End point values
    		 1_rhNGF10_Phase 1_treatment 2_rhNGF20_Phase 1_treatment 3_vehicle group_Phase 1_treatment 4_rhNGF10_Phase 2_treatment 5_rhNGF20_Phase 2_treatment 6_vehicle group_Phase 2_treatment
    Number of subjects analysed
    7
    7
    4
    52
    52
    52
    Units: 0-100%
        Vitreous
    0
    0
    25
    2
    0
    0
        Retina macula
    0
    0
    0
    0
    2
    0
        Choroid
    0
    0
    25
    0
    0
    0
        Optic nerve
    0
    0
    0
    0
    0
    0
    Attachments
    		 14.3.8.1a Summary of Fundus Ophthalmoscopy_Phase 1
    14.3.8.1b Summary of Fundus Ophthalmoscopy_Phase2
    No statistical analyses for this end point

    Secondary: anti -NGF antibodies

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    End point title
    		 anti -NGF antibodies [5]
    End point description
    Shifts from Baseline to post-Baseline visits for anti-NGF antibodies for the Safety population during the controlled treatment period (week 8 values) and follow-up period (20 weeks values) for phase 2 arms are hereto reported (as percentage from positive to positive).
    End point type
    Secondary
    End point timeframe
    period 2 (Follow Up period of 12 weeks, untill week 20)
    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: This endpoint is evaluated only for the selected group : all the available results have been reported.
    End point values
    		 4_rhNGF10_Phase 2_treatment 4_rhNGF10_Phase 2_FU 5_rhNGF20_Phase 2_treatment 5_rhNGF20_Phase 2_FU 6_vehicle group_Phase 2_treatment 6_vehicle group_Phase 2_FU
    Number of subjects analysed
    52
    45
    52
    39
    52
    48
    Units: percentage
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    treatment period (8 weeks) and follow up period (12 weeks) for Phase 1 and Phase 2 patients.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    1_rhNGF10_Phase 1
    Reporting group description
    		 cohort1: active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF).

    Reporting group title
    2_rhNGF20_Phase 1
    Reporting group description
    		 cohort 2: active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

    Reporting group title
    3_vehicle group_Phase 1
    Reporting group description
    		 cohort 1 and 2: vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period

    Reporting group title
    4_rhNGF10_Phase 2
    Reporting group description
    		 active treatment with rhNGF 10 μg/ml. One drop six times a day (one 35 μl drop equals to 0.35 μg of rhNGF)

    Reporting group title
    5_rhNGF20_Phase 2
    Reporting group description
    		 active treatment with rhNGF 20 μg/ml. One drop 6 times a day (one 35 μl drop equals to 0.70 μg of rhNGF)

    Reporting group title
    6_vehicle group_Phase 2
    Reporting group description
    		 vehicle control arm. Ophthalmic solution of the same composition as the test product with the exception of rhNGF. One drop six times a day for the entire period

    Serious adverse events
    		 1_rhNGF10_Phase 1 2_rhNGF20_Phase 1 3_vehicle group_Phase 1 4_rhNGF10_Phase 2 5_rhNGF20_Phase 2 6_vehicle group_Phase 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 7 (14.29%)
    3 / 4 (75.00%)
    13 / 52 (25.00%)
    14 / 52 (26.92%)
    4 / 52 (7.69%)
         number of deaths (all causes)
    0
    0
    0
    5
    2
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
    Additional description: Reporting groups 4 and 5: severe SAE
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Vascular disorders
    Aortic dissection
    Additional description: Reporting group 5: Severe SAE
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic rupture
    Additional description: reporting group 5: Severe SAE
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Diabetic vascular disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
    Additional description: reporting group 5: Severe SAE
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 52 (1.92%)
    3 / 52 (5.77%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    1 / 1
    0 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Corneal graft rejection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Respiratory distress
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
    Additional description: reporting groups 6 and 7 : Severe SAE
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Dyspnoea
    Additional description: reporting group 5: Severe SAE
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
    Additional description: patient of reporting group 4 had a severe SAE
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Arrhythmia
    Additional description: reporting group 4: Severe SAE
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual acuity reduced
    Additional description: visual acuity reduction of 13 letters
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    2 / 52 (3.85%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corneal endotheliitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corneal epithelium defect
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corneal oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corneal neovascularisation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corneal opacity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurotrophic keratopathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticular perforation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Renal colic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder prolapse
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corneal abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes ophthalmic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         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: 5%
    Non-serious adverse events
    		 1_rhNGF10_Phase 1 2_rhNGF20_Phase 1 3_vehicle group_Phase 1 4_rhNGF10_Phase 2 5_rhNGF20_Phase 2 6_vehicle group_Phase 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 7 (42.86%)
    5 / 7 (71.43%)
    1 / 4 (25.00%)
    23 / 52 (44.23%)
    23 / 52 (44.23%)
    21 / 52 (40.38%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Venous thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Aortic rupture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Diabetic vascular disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Diastolic hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    4 / 52 (7.69%)
    4 / 52 (7.69%)
    6 / 52 (11.54%)
         occurrences all number
    2
    0
    1
    4
    6
    6
    Fatigue
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Instillation site pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Irritability
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Instillation site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Impaired healing
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Immune system disorders
    Corneal graft rejection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    3 / 52 (5.77%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    1
    4
    1
    Immunodeficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory distress
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Investigations
    Haematocrit decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Intraocular pressure increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    4 / 52 (7.69%)
    0 / 52 (0.00%)
         occurrences all number
    2
    0
    0
    2
    4
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Blood creatine increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Heart rate increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vital dye staining cornea present
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Laceration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Periorbital haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Suture related complication
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Clavicle fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Facial bones fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Femur fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pelvic fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tibia fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Transplant failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Arrhythmia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Myocardial infarction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Cardiac failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    headache
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    4 / 52 (7.69%)
    2 / 52 (3.85%)
         occurrences all number
    0
    3
    0
    2
    4
    2
    Hypoaesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Burning sensation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Syncope
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Ear pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eye disorders
    eye pain
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 7 (42.86%)
    1 / 4 (25.00%)
    2 / 52 (3.85%)
    7 / 52 (13.46%)
    5 / 52 (9.62%)
         occurrences all number
    0
    6
    2
    2
    7
    7
    eye inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    2
    1
    0
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    2 / 52 (3.85%)
    5 / 52 (9.62%)
    2 / 52 (3.85%)
         occurrences all number
    4
    1
    1
    2
    5
    2
    Photophobia
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 7 (42.86%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    3
    0
    2
    0
    1
    Conjunctival hyperaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
         occurrences all number
    2
    0
    0
    2
    1
    1
    Corneal epithelium defect
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    5 / 52 (9.62%)
    1 / 52 (1.92%)
         occurrences all number
    0
    2
    0
    1
    5
    2
    Corneal lesion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    1 / 52 (1.92%)
    3 / 52 (5.77%)
         occurrences all number
    0
    1
    0
    2
    1
    3
    Erythema of eyelid
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    eye irritation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    0
    2
    1
    1
    eyelid margin crusting
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Foreign body sensation in eyes
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    Iridocyclitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Photopsia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    4 / 52 (7.69%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    4
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    0
    1
    2
    0
    2
    vitreous haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    Corneal decompensation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Corneal oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Keratitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    4 / 52 (7.69%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    6
    0
    ocular hyperemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    2 / 52 (3.85%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    retinal haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blepharitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    3 / 52 (5.77%)
    6 / 52 (11.54%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    3
    6
    2
    Eye pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    2
    1
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    3 / 52 (5.77%)
    0 / 52 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    0
    0
    3
    0
    2
    Lacrimation decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Corneal deposits
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Eye discharge
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    Abnormal sensation in eye
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Asthenopia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    Corneal endotheliitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Corneal opacity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Eye allergy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Eyelid pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Eyelid ptosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Lagophthalmos
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    macular fibrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ocular discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Posterior capsule opacification
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Lenticular opacities
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Meibomianitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pseudopterygium
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Retinal cyst
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Cataract
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    3 / 52 (5.77%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    Corneal erosion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    5
    1
    0
    Corneal neovascularisation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    2 / 52 (3.85%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    2
    4
    1
    Neurotrophic keratopathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Diverticular perforation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastric polyps
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    dry skin
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    onychoclasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Diabetic foot
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    Bladder prolapse
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infections and infestations
    influenza
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Keratitis herpetic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 52 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    Corneal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    4 / 52 (7.69%)
    3 / 52 (5.77%)
    2 / 52 (3.85%)
         occurrences all number
    0
    0
    0
    4
    4
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Conjunctivitis bacterial
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Corneal abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Diverticulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    oral herpes
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Staphylococcal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Herpes ophthalmic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 52 (3.85%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    blister infected
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Catheter site infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Herpes simplex ophtalmic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Herpes zoster ophtalmic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Onychomycosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Folate deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Iron deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Decreased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jan 2013
    Protocol Amendment #1: the main changes to the protocol are listed below • Change in the study title • Change in the study population • Deletion of inclusion criteria #7 • Addition of exclusion criteria #1 • Specify that additional safety information continued to be collected within 4 weeks after the end of treatment • Further clarify the study design shown in Figures 1 and 2 • Clarify the definition of deterioration and modify a secondary efficacy variable • Add an exploratory efficacy variable • Add that the grade of corneal fluorescein staining using the modified Oxford scale should be assessed at all visits where corneal fluorescein staining is performed • Add the laboratory that was in charge of the processing, storage and shipment of immunogenicity evaluation samples and the reading center in charge of the collection, classification and evaluation of the corneal photos
    02 Dec 2013
    Amendment #2: main chages to the study protocol are listed below: • Permit a single additional course of treatment with rhNGF to patients experiencing a recurrent PED or corneal ulcer immediately after 8 weeks of treatment with study medications • Enlarge the visual acuity entry criteria • Permit treatment with preservative free antiviral eye drops to patients during the 8-week controlled treatment period that were considered to be at imminent risk of deterioration of their Stage 2 or 3 NK in the opinion of the Investigator • Reflect sponsor organizational changes in regards to the pharmacovigilance main contact and in regards to the laboratory that was in charge of the PK analysis
    31 Mar 2014
    Amendment #3: main changes are listed below. • Change in the assessment of the primary variable from the evaluation of thePED or corneal ulcer lesion done by the Investigator to the evaluation done by the central reading center. Consequently to this major change, the evaluation of thePED or corneal ulcer done by the Investigator at Week 4 was moved into the secondary variables and the assessment of complete healing of the PED or corneal ulcer determined by the reading center at Weeks 6 and 8 was moved from exploratory variables to secondary variables. • Changed the primary endpoint to be the last observation carried forward (LOCF), where it had previously used no imputation • The secondary efficacy endpoints related to the controlled treatment period concerning the percentage of patients experiencing complete corneal clearing at Weeks4,6 and8 were moved from the exploratory efficacy variables to the secondary efficacy variables. • Added clarification about data to be reported in the main CSR and an addendum to the CSR. The database was locked and the study was completed after the last patient had completed 12 weeks of the follow-up period. However, after the database lock, patients continued with scheduled visits for the remainder of the 48- or 56-week follow-up period and the long term safety/efficacy data collected during these followup visits will be described in an addendum to the final main CSR. • Added clarification that the results for patients enrolled during the PhaseI segment of the study were analyzed separately from the results for patients enrolled during the PhaseII segment of the study • Added further specification about the handling of missing data • Added text for sponsor organizational changes:Change of the name of the Sponsor from Dompé s.p.a. to Dompé farmaceutici s.p.a.;Change of the pharmacovigilance main contact;Change of the medical expert;inclusion of a clinical development specialist,Administrative changes

    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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