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    Clinical Trial Results:
    A 8 weeks, Phase II, single-centre, randomized, double-masked, vehicle-controlled, parallel group study with 4 weeks of follow-up to evaluate preliminary efficacy and safety of recombinant human Nerve Growth Factor (rhNGF) eye drops solution versus vehicle in patients after cataract and refractive surgery.

    Summary
    EudraCT number
    		 2016-002172-27
    Trial protocol
    		 IT  
    Global end of trial date
    04 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jun 2019
    First version publication date
    16 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NGF0116
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03035864
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dompé farmaceutici s.p.a.
    Sponsor organisation address
    Via Santa Lucia 6, Milan, Italy, 20122
    Public contact
    CLINICAL DEVELOPMENT, DOMPE' FARMACEUTICI SPA, +39 02583831, info@dompe.com
    Scientific contact
    CLINICAL DEVELOPMENT, DOMPE' FARMACEUTICI SPA, +39 02583831, info@dompe.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2017
    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 efficacy and safety of rhNGF when administered as eye drops to patients after cataract and refractive surgery.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jan 2017
    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
    Italy: 180
    Worldwide total number of subjects
    180
    EEA total number of subjects
    180
    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)
    173
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 180 patients were screened and all of them were randomized to the assigned treatment: 120 patients were randomised to receive rhNGF and 60 were randomised to receive vehicle. A total of 160 patients (88.9% of screened patients), 105 (87.5%) in the rhNGF group and 55 (91.7%) in the vehicle group, completed the study.

    Pre-assignment
    Screening details
    		 After successful completion of screening, each eligible patient was assigned a consecutive randomisation number from the randomization list (randomization number) according to the sequence of study entry (randomization), from 001 to 180. Drop outs were not to be replaced after randomization.

    Period 1
    Period 1 title
    Treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    It is a double-masked study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 rhNGF
    Arm description
    		 rhNGF 20 μg/mL. One drop (40 μL) corresponding to 0.80 μg of rhNGF was instilled into each eligible eye six times a day (every 2 hours), for a total daily dose of 9.6 μg (both eyes, if applicable), for 56 consecutive days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhNGF
    Investigational medicinal product code
    Other name
    recombinant human nerve growth factor
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Recombinant human Nerve Growth Factor (rhNGF) 20 μg/mL vials. Dosage: One drop (40 μL) corresponding to 0.80 μg of rhNGF was instilled into each eligible eye (in both eyes, if applicable) six times a day (every 2 hours), for a total daily dose of 9.6 μg (in both eyes, if applicable), for 56 consecutive days. Total dose was 537.6 μg/56 days if both eyes were treated.

    Arm title
    		 Vehicle
    Arm description
    		 Vehicle. One drop (40 μL) was instilled into each eligible eye six times a day (every 2 hours), for 56 consecutive days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    vehicle
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Vehicle vials. Dosage: One drop (40 μL) was instilled into each eligible eye (in both eyes, if applicable) six times a day (every 2 hours).

    Number of subjects in period 1
    		rhNGF Vehicle
    Started
    120
    60
    Completed
    116
    59
    Not completed
    4
    1
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    1
    -
    Period 2
    Period 2 title
    Follow-up period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    It is a double-masked study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 rhNGF
    Arm description
    		 Patients randomized to rhNGF eye drops solution in the 8 weeks treatment period underwent a 4 weeks follow-up period with no further treatment.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Vehicle
    Arm description
    		 Patients randomized to the vehicle in the 8 weeks treatment period underwent a 4 weeks follow-up period with no further treatment.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		rhNGF Vehicle
    Started
    116
    59
    Completed
    105
    55
    Not completed
    11
    4
         Consent withdrawn by subject
    3
    2
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    6
    2
         Decision unrelated to an adverse event
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    rhNGF
    Reporting group description
    		 rhNGF 20 μg/mL. One drop (40 μL) corresponding to 0.80 μg of rhNGF was instilled into each eligible eye six times a day (every 2 hours), for a total daily dose of 9.6 μg (both eyes, if applicable), for 56 consecutive days.

    Reporting group title
    Vehicle
    Reporting group description
    		 Vehicle. One drop (40 μL) was instilled into each eligible eye six times a day (every 2 hours), for 56 consecutive days.

    Reporting group values
    		 rhNGF Vehicle Total
    Number of subjects
    		 120 60 180
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 115 58 173
        From 65-84 years
    		 5 2 7
    Gender categorical
    Units: Subjects
        Female
    		 73 33 106
        Male
    		 47 27 74
    Subject analysis sets

    Subject analysis set title
    rhNGF - SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety set (SAF): the Safety Set was defined as all enrolled patients who received at least one dose of the IMP (rhNGF) at the study eye(s).

    Subject analysis set title
    Vehicle - SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety set (SAF): the Safety Set was defined as all enrolled patients who received at least one dose of the IMP (vehicle) at the study eye(s).

    Subject analysis set title
    rhNGF - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS): the FAS was defined as all patients in the SAF, who had at least one post-baseline efficacy measurement in a study eye.

    Subject analysis set title
    Vehicle - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS): the FAS was defined as all patients in the SAF, who had at least one post-baseline efficacy measurement in a study eye

    Subject analysis sets values
    		 rhNGF - SAF Vehicle - SAF rhNGF - FAS Vehicle - FAS
    Number of subjects
    115
    59
    112
    58
    Age categorical
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    71
    33
        Male
    44
    26

    End points

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    End points reporting groups
    Reporting group title
    rhNGF
    Reporting group description
    		 rhNGF 20 μg/mL. One drop (40 μL) corresponding to 0.80 μg of rhNGF was instilled into each eligible eye six times a day (every 2 hours), for a total daily dose of 9.6 μg (both eyes, if applicable), for 56 consecutive days.

    Reporting group title
    Vehicle
    Reporting group description
    		 Vehicle. One drop (40 μL) was instilled into each eligible eye six times a day (every 2 hours), for 56 consecutive days.
    Reporting group title
    rhNGF
    Reporting group description
    		 Patients randomized to rhNGF eye drops solution in the 8 weeks treatment period underwent a 4 weeks follow-up period with no further treatment.

    Reporting group title
    Vehicle
    Reporting group description
    		 Patients randomized to the vehicle in the 8 weeks treatment period underwent a 4 weeks follow-up period with no further treatment.

    Subject analysis set title
    rhNGF - SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety set (SAF): the Safety Set was defined as all enrolled patients who received at least one dose of the IMP (rhNGF) at the study eye(s).

    Subject analysis set title
    Vehicle - SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety set (SAF): the Safety Set was defined as all enrolled patients who received at least one dose of the IMP (vehicle) at the study eye(s).

    Subject analysis set title
    rhNGF - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS): the FAS was defined as all patients in the SAF, who had at least one post-baseline efficacy measurement in a study eye.

    Subject analysis set title
    Vehicle - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS): the FAS was defined as all patients in the SAF, who had at least one post-baseline efficacy measurement in a study eye

    Primary: Change From Baseline in SANDE Scores for Frequency and Severity Assessed at 8 Weeks of Treatment.

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    End point title
    		 Change From Baseline in SANDE Scores for Frequency and Severity Assessed at 8 Weeks of Treatment.
    End point description
    The Symptom Assessment in Dry Eye (SANDE) questionnaire is a short questionnaire to evaluate both dry eye intensity and frequency by using a 100 mm visual analogue scale (VAS). The patient symptoms of ocular dryness and/or irritation were quantified on the scale based on two questions that assessed both severity and frequency of symptoms. If at least one SANDE assessment was missing at Week 8, the values of the last post-baseline assessment (including those from unscheduled visits) with non-missing values for frequency and severity were imputed (last observation carried forward, LOCF).
    End point type
    Primary
    End point timeframe
    Week 8
    End point values
    		 rhNGF - FAS Vehicle - FAS
    Number of subjects analysed
    112
    58
    Units: mm
    arithmetic mean (standard deviation)
        Frequency
    -37.2 ± 24.85
    -35.7 ± 26.04
        Severity
    -37.8 ± 27.20
    -37.3 ± 20.43
    Statistical analysis title
    		 rhNGF vs Vehicle
    Statistical analysis description
    Statistical analysis related to "frequency"
    Comparison groups
    Vehicle - FAS v rhNGF - FAS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.974
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.85
         upper limit
    		 6.63
    Notes
    [1] - The comparison between groups will be performed with an exploratory analysis of covariance (ANCOVA) model at a 5% level, considering treatment and eye subgroup (1 vs. 2 study eyes treated) as factors and respective baseline values as covariate.
    Statistical analysis title
    		 rhNGF vs Vehicle
    Statistical analysis description
    Statistical analysis related to "severity"
    Comparison groups
    rhNGF - FAS v Vehicle - FAS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.399
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    2.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.85
         upper limit
    		 9.61
    Notes
    [2] - The comparison between groups will be performed with an exploratory analysis of covariance (ANCOVA) model at a 5% level, considering treatment and eye subgroup (1 vs. 2 study eyes treated) as factors and respective baseline values as covariate.

    Primary: Changes in Corneal Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at 8 weeks of treatment

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    End point title
    		 Changes in Corneal Vital Staining With Fluorescein (National Eye Institute [NEI] Scales) at 8 weeks of treatment
    End point description
    Corneal Staining was derived as sum of scores of the five corneal sectors (central, superior, inferior nasal and temporal) each of which was scored on a scale of 0–3, with a maximal score of 15. If at least one assessment was missing at Week 8, the values of the last post-baseline assessment (including those from unscheduled visits) with non-missing values were imputed (last observation carried forward, LOCF).
    End point type
    Primary
    End point timeframe
    Week 8
    End point values
    		 rhNGF - FAS Vehicle - FAS
    Number of subjects analysed
    112
    58
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.5 ± 2.11
    -2.2 ± 1.81
    Statistical analysis title
    		 rhNGF vs Vehicle
    Comparison groups
    Vehicle - FAS v rhNGF - FAS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.214
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.1
    Notes
    [3] - The comparison between groups will be performed with an exploratory analysis of covariance (ANCOVA) model at a 5% level, considering treatment and eye subgroup (1 vs. 2 study eyes treated) as factors and respective baseline values as covariate.

    Secondary: Changes in Conjunctival Vital Staining With Fluorescein (National Eye Institute [NEI] Scales)

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    End point title
    		 Changes in Conjunctival Vital Staining With Fluorescein (National Eye Institute [NEI] Scales)
    End point description
    Conjunctival Staining was derived as sum of scores of the conjunctival area (nasal-superior paralimbal, nasal-inferior paralimbal, nasal-peripheral, temporal-superior paralimbal, temporal-inferior paralimbal, temporal-peripheral) with a grading scale of 0–3 and with a maximal score of 9 for the nasal and temporal conjunctiva. Data for the main eye are reported.
    End point type
    Secondary
    End point timeframe
    From baseline to weeks 4, 8 and 12
    End point values
    		 rhNGF - FAS Vehicle - FAS
    Number of subjects analysed
    112 [4]
    58 [5]
    Units: units on a scale
    arithmetic mean (standard deviation)
        week 4
    0.0 ± 0.0
    0.0 ± 0.0
        week 8
    0.0 ± 0.0
    0.0 ± 0.0
        week 12
    0.0 ± 0.0
    0.0 ± 0.0
    Notes
    [4] - Week 4 = 110 Week 8 = 107 Week 12 = 107
    [5] - Week 4 = 58 Week 8 = 58 Week 12 = 55
    No statistical analyses for this end point

    Secondary: Changes in Tear Film Break-Up Time (TFBUT)

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    End point title
    		 Changes in Tear Film Break-Up Time (TFBUT)
    End point description
    The TFBUT measurement was performed after instillation of 5 microliters of 2% sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film. Data for the main eye are reported.
    End point type
    Secondary
    End point timeframe
    From baseline to weeks 4, 8 and 12
    End point values
    		 rhNGF - FAS Vehicle - FAS
    Number of subjects analysed
    112 [6]
    58 [7]
    Units: seconds
    arithmetic mean (standard deviation)
        Week 4
    2.5 ± 3.07
    2.5 ± 2.37
        Week 8
    1.9 ± 2.96
    2.2 ± 2.67
        Week 12
    2.3 ± 2.61
    2.7 ± 2.72
    Notes
    [6] - Week 4 = 110 Week 8 = 107 Week 12 = 107
    [7] - Week 4 = 58 Week 8 = 58 Week 12 = 55
    No statistical analyses for this end point

    Secondary: Changes in Cochet-Bonnet corneal aesthesiometry

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    End point title
    		 Changes in Cochet-Bonnet corneal aesthesiometry
    End point description
    Corneal sensation was measured in both eyes in each of the four quadrants of the cornea using the Cochet Bonnet aesthesiometer before the instillation of any dilating or anesthetic eye drops. Data for the main eye are reported.
    End point type
    Secondary
    End point timeframe
    From baseline to week 8
    End point values
    		 rhNGF - FAS Vehicle - FAS
    Number of subjects analysed
    112 [8]
    58 [9]
    Units: cm
    arithmetic mean (standard deviation)
        Superior nasal
    -0.1 ± 0.31
    -0.2 ± 0.31
        Inferior nasal
    -0.2 ± 0.32
    -0.1 ± 0.64
        Superior temporal
    -0.2 ± 0.36
    -0.2 ± 0.34
        Inferior temporal
    -0.1 ± 0.41
    0.0 ± 0.64
    Notes
    [8] - Superior nasal = 107 Inferior nasal = 107 Superior temporal = 107 Inferior temporal = 107
    [9] - Superior nasal = 58 Inferior nasal = 58 Superior temporal = 58 Inferior temporal = 58
    No statistical analyses for this end point

    Secondary: Changes in SANDE scores (face values) for frequency and severity

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    End point title
    		 Changes in SANDE scores (face values) for frequency and severity
    End point description
    The Symptom Assessment in Dry Eye (SANDE) questionnaire is a short questionnaire to evaluate both dry eye intensity and frequency by using a 100 mm visual analogue scale (VAS). The patient symptoms of ocular dryness and/or irritation were quantified on the scale based on two questions that assessed both severity and frequency of symptoms.
    End point type
    Secondary
    End point timeframe
    From baseline to weeks 4, 8 and 12
    End point values
    		 rhNGF - FAS Vehicle - FAS
    Number of subjects analysed
    112 [10]
    58 [11]
    Units: mm
    arithmetic mean (standard deviation)
        Frequency - week 4
    -35.1 ± 22.37
    -33.2 ± 25.18
        Frequency - week 8
    -37.2 ± 24.84
    -35.7 ± 26.04
        Frequency - week 12
    -42.1 ± 22.94
    -38.6 ± 26.25
        Severity - week 4
    -35.7 ± 24.28
    -32.9 ± 20.03
        Severity - week 8
    -37.9 ± 27.51
    -37.3 ± 20.43
        Severity- week 12
    -43.5 ± 22.27
    -38.4 ± 20.23
    Notes
    [10] - Frequency wk 4 = 110 Fr wk 8 & 12 = 107 Severity wk 4 = 110 Sev wk 8 & 12 = 107
    [11] - Frequency Wk 4 & 8 = 58 Fr Wk 12 = 55 Severity Wk 4 & 8 = 58 Sev Wk 12 = 55
    Statistical analysis title
    		 rhNGF vs Vehicle
    Statistical analysis description
    Frequency - week 4
    Comparison groups
    rhNGF - FAS v Vehicle - FAS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.881
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.13
         upper limit
    		 5.27
    Notes
    [12] - Analysis results from an Analysis of Covariance (ANCOVA) with Treatment and Number of Study Eyes as factor and Baseline as covariate.
    Statistical analysis title
    		 rhNGF vs Vehicle
    Statistical analysis description
    Frequency - week 8
    Comparison groups
    rhNGF - FAS v Vehicle - FAS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.926
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.96
         upper limit
    		 6.33
    Notes
    [13] - Analysis results from an Analysis of Covariance (ANCOVA) with Treatment and Number of Study Eyes as factor and Baseline as covariate.
    Statistical analysis title
    		 rhNGF vs Vehicle
    Statistical analysis description
    Frequency - week 12
    Comparison groups
    rhNGF - FAS v Vehicle - FAS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.426
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -2.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.97
         upper limit
    		 3.38
    Notes
    [14] - Analysis results from an Analysis of Covariance (ANCOVA) with Treatment and Number of Study Eyes as factor and Baseline as covariate.
    Statistical analysis title
    		 rhNGF vs Vehicle
    Statistical analysis description
    Severity - week 4
    Comparison groups
    rhNGF - FAS v Vehicle - FAS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.828
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.04
         upper limit
    		 6.29
    Notes
    [15] - Analysis results from an Analysis of Covariance (ANCOVA) with Treatment and Number of Study Eyes as factor and Baseline as covariate.
    Statistical analysis title
    		 rhNGF vs Vehicle
    Statistical analysis description
    Severity - week 8
    Comparison groups
    rhNGF - FAS v Vehicle - FAS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.394
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    2.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.75
         upper limit
    		 9.47
    Notes
    [16] - Analysis results from an Analysis of Covariance (ANCOVA) with Treatment and Number of Study Eyes as factor and Baseline as covariate.
    Statistical analysis title
    		 rhNGF vs Vehicle
    Statistical analysis description
    Severity - week 12
    Comparison groups
    rhNGF - FAS v Vehicle - FAS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.552
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.41
         upper limit
    		 3.44
    Notes
    [17] - Analysis results from an Analysis of Covariance (ANCOVA) with Treatment and Number of Study Eyes as factor and Baseline as covariate.

    Secondary: Changes from baseline in corneal vital staining with 
fluorescein (NEI scales) at the other time points

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    End point title
    		 Changes from baseline in corneal vital staining with 
fluorescein (NEI scales) at the other time points
    End point description
    Corneal Staining was derived as sum of scores of the five corneal sectors (central, superior, inferior nasal and temporal) each of which was scored on a scale of 0–3, with a maximal score of 15. Data for the main eye are reported.
    End point type
    Secondary
    End point timeframe
    At weeks 4, 12
    End point values
    		 rhNGF - FAS Vehicle - FAS
    Number of subjects analysed
    112 [18]
    58 [19]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4
    -2.4 ± 2.17
    -2.1 ± 1.85
        Week 12
    -2.5 ± 2.12
    -2.2 ± 1.83
    Notes
    [18] - n=110 at week 4 n=107 at week 12
    [19] - n=55 at week 12
    Statistical analysis title
    		 rhNGF vs Vehicle at week 4
    Comparison groups
    Vehicle - FAS v rhNGF - FAS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.487
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.18
    Notes
    [20] - The comparison between groups will be performed with an exploratory analysis of covariance (ANCOVA) model at a 5% level, considering treatment and eye subgroup (1 vs. 2 study eyes treated) as factors and respective baseline values as covariate.
    Statistical analysis title
    		 RhNGF vs Vehicle at week 12
    Comparison groups
    rhNGF - FAS v Vehicle - FAS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.593
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.03
    Notes
    [21] - The comparison between groups will be performed with an exploratory analysis of covariance (ANCOVA) model at a 5% level, considering treatment and eye subgroup (1 vs. 2 study eyes treated) as factors and respective baseline values as covariate.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At day 0 (baseline), at weeks 4, 8, and 12 (follow-up visit)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    rhNGF - SAF
    Reporting group description
    		 Safety set (SAF): the Safety Set was defined as all enrolled patients who received at least one dose of the IMP (rhNGF) at the study eye(s).

    Reporting group title
    Vehicle - SAF
    Reporting group description
    		 Safety set (SAF): the Safety Set was defined as all enrolled patients who received at least one dose of the IMP (vehicle) at the study eye(s).

    Serious adverse events
    		 rhNGF - SAF Vehicle - SAF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.9%
    Non-serious adverse events
    		 rhNGF - SAF Vehicle - SAF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 115 (43.48%)
    19 / 59 (32.20%)
    Injury, poisoning and procedural complications
    Eye burns
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Corneal abrasion
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 115 (7.83%)
    0 / 59 (0.00%)
         occurrences all number
    14
    0
    Burning sensation
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    DIzziness
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Swelling
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    23 / 115 (20.00%)
    2 / 59 (3.39%)
         occurrences all number
    33
    2
    Eye irritation
         subjects affected / exposed
    13 / 115 (11.30%)
    10 / 59 (16.95%)
         occurrences all number
    21
    12
    Vision blurred
         subjects affected / exposed
    7 / 115 (6.09%)
    10 / 59 (16.95%)
         occurrences all number
    7
    12
    Myopia
         subjects affected / exposed
    10 / 115 (8.70%)
    4 / 59 (6.78%)
         occurrences all number
    10
    4
    Dry eye
         subjects affected / exposed
    6 / 115 (5.22%)
    6 / 59 (10.17%)
         occurrences all number
    8
    11
    Eye swelling
         subjects affected / exposed
    4 / 115 (3.48%)
    2 / 59 (3.39%)
         occurrences all number
    5
    2
    Photophobia
         subjects affected / exposed
    3 / 115 (2.61%)
    3 / 59 (5.08%)
         occurrences all number
    4
    3
    Eyelid oedema
         subjects affected / exposed
    3 / 115 (2.61%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Foreign body sensation in eyes
         subjects affected / exposed
    2 / 115 (1.74%)
    1 / 59 (1.69%)
         occurrences all number
    2
    1
    Visual impairment
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 59 (1.69%)
         occurrences all number
    1
    2
    Diplopia
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Eye pruritus
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Ocular hyperaemia
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Blepharospasm
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    2
    Conjunctival irritation
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Corneal epithelium defect
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Ocular discomfort
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Photopsia
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Toothache
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Dyspepsia
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinalgia
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Nasal dryness
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Influenza
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Ear infection
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Nov 2016
    • The use of SANDE scoring system was updated and clarified • The exclusion criterion No. 2 was modified with the specification that particular attention was to be paid to malignancies and neuro-oncological diseases • A pregnancy test was added at Week 4 as per Clinical Trial Facilitation Group (CTFG) guideline • The definition of accepted/forbidden medications was updated • Criteria for study discontinuation were modified with the addition of safety concerns related to IMP • The list of conditions which should not have to be considered, SAEs was modified • Other minor changes or typographical errors correction were performed
    12 Apr 2017
    The secondary efficacy endpoint “Changes in Cornea vital staining with fluorescein (NEI scales)” was removed and was modified into a Co-Primary Efficacy Endpoint.

    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.
    There are no limitations or caveats to this summary of results
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