Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44366   clinical trials with a EudraCT protocol, of which   7389   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Multicenter, Randomized, Double-Masked, Placebo-Controlled Phase II Study to evaluate the Safety and Efficacy of Pro-ocular™ 0.5% and 1% in Patients with Dry Eye Syndrome

    Summary
    EudraCT number
    		 2019-000747-27
    Trial protocol
    		 IT  
    Global end of trial date
    26 Oct 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jan 2026
    First version publication date
    07 Jan 2026
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    049/SI
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04645446
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    SIFI S.p.A.
    Sponsor organisation address
    Via Ercole Patti 36, Aci Sant’Antonio, Catania, Italy,
    Public contact
    LAURA BONINO, SOCIETA' INDUSTRIA FARMACEUTICA ITALIANA (SIFI) s.p.a, clinicaldevelopment@sifigroup.com
    Scientific contact
    LAURA BONINO, SOCIETA' INDUSTRIA FARMACEUTICA ITALIANA (SIFI) s.p.a, clinicaldevelopment@sifigroup.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
    29 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Oct 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the efficacy of progesterone topical gel (0.5% and 1%) compared to placebo gel, when administered twice a day for 3 months (12 weeks) in patients with moderate to severe dry eye syndrome.
    Protection of trial subjects
    This trial was conducted in accordance with the Declaration of Helsinki, ICH-GCP E6(R2), and applicable national regulations. Ethical approval was obtained from all relevant Italian Ethics Committees prior to study initiation. All participants provided written informed consent before undergoing any study-related procedures. For patients unable to read, an impartial witness was present during the consent process. The study design included strict inclusion and exclusion criteria to ensure participant safety and scientific integrity. Adverse events (AEs) were systematically recorded and evaluated. Blinding and randomization were centrally managed to protect against bias, and data confidentiality was maintained throughout. Essential documents were archived per GCP standards. The study was monitored and audited by an independent CRO to ensure compliance and data integrity.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Placebo was used as a comparator. The study design, being a multicenter, randomised, double-masked, placebo-controlled, Phase II superiority study is considered as the most suitable design to evaluate the potential efficacy and safety of Pro-ocular™ topical gel. The placebo control allowed for unbiased assessment of treatment effects in the absence of a universally accepted standard therapy for dry eye syndrome.
    Actual start date of recruitment
    18 Feb 2021
    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: 91
    Worldwide total number of subjects
    91
    EEA total number of subjects
    91
    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)
    50
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Start of Recruitment (FPFV): 18 February 2021 - End of Trial (LPLV): 26 October 2022 - Trial Completion (Last Site Close-Out Visit): 27 April 2023 Study conducted in 4 sites in Italy: Ospedale Luigi Sacco, MI, AOU Careggi, FI, Policlinico G. Martino, ME, Ospedale San Marco, CT.

    Pre-assignment
    Screening details
    		 101 subjects pre-screened: 5 withdrawal prior enrolment; 96 enrolled; 5 failure; 91 randomized. Screening included 15-day wash-out for anti-inflammatory topical treatments and 7-day for contact lenses. Exclusions due to withdrawal, lost to follow-up, or protocol criteria. Inclusion: age ≥18, dry eye ≥3 months, NEI >3, TBUT ≤5s, Schirmer’s 1–10

    Pre-assignment period milestones
    Number of subjects started
    		 96 [1]
    Number of subjects completed
    		 91

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Lost to Follow Up: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Reason: Number of subjects
    		 Physician Decision: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In enrolled patient count, 5 withdrawal prior enrolment were not included. Please also refer to screening details field in pre-assignment period.
    Period 1
    Period 1 title
    Interventional Phase (overall 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
    Blinding was maintained by centralized randomization via IWRS. Identical appearance, packaging, and administration of active and placebo gels. Placebo contained titanium dioxide instead of progesterone, but was otherwise indistinguishable. Emergency unblinding was allowed via IWRS only in medical emergencies.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pro-ocular™ 0.5%
    Arm description
    		 Pro-ocular™ 0.5% topical gel (0.35 mg progesterone/dose, BID to forehead for 12 weeks) was tested in adults with moderate to severe dry eye.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pro-ocular™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Ocular use
    Dosage and administration details
    0.35 mg progesterone/dose, BID to forehead for 12 weeks

    Arm title
    		 Pro-ocular™ 1%
    Arm description
    		 Pro-ocular™ 1% topical gel (0.7 mg progesterone/dose, BID to forehead for 12 weeks) was tested in adults with moderate to severe dry eye.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pro-ocular™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Ocular use
    Dosage and administration details
    0.7 mg progesterone/dose, BID to forehead for 12 weeks

    Arm title
    		 Placebo
    Arm description
    		 Placebo topical gel (no active ingredient; titanium dioxide instead of progesterone), identical in appearance and dosing to active gel (0.07g BID to forehead for 12 weeks).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Ocular use
    Dosage and administration details
    0.07g BID to forehead for 12 weeks

    Number of subjects in period 1
    		Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Started
    31
    30
    30
    Completed
    24
    27
    26
    Not completed
    7
    3
    4
         Consent withdrawn by subject
    4
    1
    -
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    -
    -
    1
         Other
    -
    -
    1
         Lost to follow-up
    2
    1
    2
         Protocol deviation
    -
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Pro-ocular™ 0.5%
    Reporting group description
    		 Pro-ocular™ 0.5% topical gel (0.35 mg progesterone/dose, BID to forehead for 12 weeks) was tested in adults with moderate to severe dry eye.

    Reporting group title
    Pro-ocular™ 1%
    Reporting group description
    		 Pro-ocular™ 1% topical gel (0.7 mg progesterone/dose, BID to forehead for 12 weeks) was tested in adults with moderate to severe dry eye.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo topical gel (no active ingredient; titanium dioxide instead of progesterone), identical in appearance and dosing to active gel (0.07g BID to forehead for 12 weeks).

    Reporting group values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo Total
    Number of subjects
    		 31 30 30 91
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.4 ( 13.85 ) 61.7 ( 10.89 ) 59 ( 9.49 ) -
    Gender categorical
    Units: Subjects
        Female
    		 28 27 27 82
        Male
    		 3 3 3 9
    Race
    Units: Subjects
        American Indian / Alaska Native
    		 1 0 0 1
        Asian
    		 0 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 0 0
        White / Caucasian
    		 29 30 29 88
        Unknown or Not Reported
    		 0 0 0 0
        Other
    		 1 0 0 1
    Smoking Status
    Units: Subjects
        Ex-Smoker
    		 3 3 3 9
        Current smoke
    		 2 0 2 4
        Non-smoker
    		 26 27 25 78
    Alcohol consumption status
    Units: Subjects
        Yes
    		 0 0 1 1
        No
    		 31 30 29 90
    Use of Chlorinated Swimming Pool More Than Twice A Week
    Units: Subjects
        Yes
    		 0 0 0 0
        No
    		 31 30 30 91
    Use of Sunscreen on The Forehead or Eye Area
    Units: Subjects
        Yes
    		 0 0 0 0
        No
    		 31 30 30 91
    Use of Contact Lenses
    Units: Subjects
        Yes
    		 1 0 0 1
        No
    		 30 30 30 90
    Duration of Smoking
    Units: Years
        arithmetic mean (standard deviation)
    		 21.3 ( 12.74 ) 33 ( 20.22 ) 34 ( 5.57 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Pro-ocular™ 0.5%
    Reporting group description
    		 Pro-ocular™ 0.5% topical gel (0.35 mg progesterone/dose, BID to forehead for 12 weeks) was tested in adults with moderate to severe dry eye.

    Reporting group title
    Pro-ocular™ 1%
    Reporting group description
    		 Pro-ocular™ 1% topical gel (0.7 mg progesterone/dose, BID to forehead for 12 weeks) was tested in adults with moderate to severe dry eye.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo topical gel (no active ingredient; titanium dioxide instead of progesterone), identical in appearance and dosing to active gel (0.07g BID to forehead for 12 weeks).

    Primary: Mean change from Baseline (Visit 1 pre-dose) in Corneal Fluorescein Staining assessed by NEI scale at Week 12 (Day 84) (with Last Observation Carried Forward [LOCF] imputation)

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in Corneal Fluorescein Staining assessed by NEI scale at Week 12 (Day 84) (with Last Observation Carried Forward [LOCF] imputation)
    End point description
    Data from Table 15 CSR
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: NEI scale points
    arithmetic mean (standard deviation)
        Baseline
    7.4 ( 3 )
    7.7 ( 2.88 )
    8.2 ( 3.47 )
        Week 12
    4.5 ( 2.92 )
    5.7 ( 3.85 )
    4.4 ( 3.20 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in Co
    Statistical analysis title
    		 Statistical analysis primary endpoint n. 1
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1 [1]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - Correzione per molteplicità: Holm-Bonferroni

    Primary: Mean change from Baseline (Visit 1 pre-dose) in sum of Frequency and Intensity of Dryness/Irritation Patient Feeling assessed by Symptom Assessment in Dry Eye (SANDE) Questionnaire at Week 12 (Day 84) (with LOCF imputation).

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in sum of Frequency and Intensity of Dryness/Irritation Patient Feeling assessed by Symptom Assessment in Dry Eye (SANDE) Questionnaire at Week 12 (Day 84) (with LOCF imputation).
    End point description
    Data from Table 15 CSR
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: SANDE scale points
    arithmetic mean (standard deviation)
        Baseline
    70.2 ( 26.01 )
    63.9 ( 29.25 )
    74.7 ( 22.97 )
        Week 12
    48.4 ( 28.23 )
    44.1 ( 32.25 )
    45.1 ( 25.62 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in su
    Statistical analysis title
    		 Statistical analysis primary endpoint n. 2
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - Correzione per molteplicità: Holm-Bonferroni

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in Corneal Fluorescein Staining assessed by NEI scale at Week 12 (Day 84).

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in Corneal Fluorescein Staining assessed by NEI scale at Week 12 (Day 84).
    End point description
    Data from Table 18 CSR. Subjects analysed reported are considered at 12 Weeks. Subjects analysed at Baseline: Pro-ocular 0.5%: 29 Pro-ocular 1%: 30 Placebo: 30
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    24
    28
    27
    Units: NEI scale points
    arithmetic mean (standard deviation)
        Baseline
    7.4 ( 3.00 )
    7.7 ( 2.88 )
    8.2 ( 3.47 )
        Week 12
    4.2 ( 2.63 )
    5.9 ( 3.83 )
    4.4 ( 3.23 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in Co
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 1
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in sum of Frequency and Intensity of dryness/irritation patient feeling assessed by SANDE questionnaire at Week 12 (Day 84).

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in sum of Frequency and Intensity of dryness/irritation patient feeling assessed by SANDE questionnaire at Week 12 (Day 84).
    End point description
    Data from Table 20 (Global Score) CSR. Subjects analysed reported are considered at 12 Weeks. Subjects analysed at Baseline: Pro-ocular 0.5%: 29 Pro-ocular 1%: 30 Placebo: 30
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    25
    28
    27
    Units: SANDE scale points
    arithmetic mean (standard deviation)
        Baseline
    70.2 ( 26.01 )
    63.9 ( 29.25 )
    74.7 ( 22.97 )
        Week 12
    46.6 ( 28.22 )
    42.8 ( 31.54 )
    44.0 ( 26.14 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in su
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 2
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in Conjunctival Fluorescein Staining assessed by NEI scale at Week 12 (Day 84) (with LOCF imputation).

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in Conjunctival Fluorescein Staining assessed by NEI scale at Week 12 (Day 84) (with LOCF imputation).
    End point description
    Data from Table 24 of CSR. Subjects analysed reported are considered at 12 Weeks. Subjects analysed at Baseline: Pro-ocular 0.5%: 29 Pro-ocular 1%: 30 Placebo: 30
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: NEI scale score
    arithmetic mean (standard deviation)
        Nasal Total Baseline
    3.7 ( 2.89 )
    4.2 ( 2.70 )
    5.0 ( 3.27 )
        Nasal Total Week 12
    2.0 ( 2.35 )
    3.3 ( 2.74 )
    3.5 ( 3.33 )
        Temporal Total Baseline
    3.3 ( 3.15 )
    3.8 ( 2.62 )
    4.5 ( 3.22 )
        Temporal Total Week 12
    1.8 ( 2.38 )
    2.7 ( 2.71 )
    3.6 ( 3.31 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in Co
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 3
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in Conjunctival Fluorescein Staining assessed by NEI scale at Week 12 (Day 84).

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in Conjunctival Fluorescein Staining assessed by NEI scale at Week 12 (Day 84).
    End point description
    Data from Table 24 of CSR.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    24
    28
    27
    Units: NEI scale score
    arithmetic mean (standard deviation)
        Nasal Total Baseline
    3.7 ( 2.89 )
    4.2 ( 2.70 )
    5.0 ( 3.27 )
        Nasal Total Week 12
    1.7 ( 1.93 )
    3.4 ( 2.77 )
    3.5 ( 3.46 )
        Temporal Total Baseline
    3.3 ( 3.15 )
    3.8 ( 2.62 )
    4.5 ( 3.22 )
        Temporal Total Week 12
    1.5 ( 1.84 )
    2.9 ( 2.73 )
    3.6 ( 3.35 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in Co
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 4
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in Corneal Fluorescein Staining assessed by NEI scale at Week 2, 4, 8 (Day 14, 28, 56) as Intermediate Study Visits

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in Corneal Fluorescein Staining assessed by NEI scale at Week 2, 4, 8 (Day 14, 28, 56) as Intermediate Study Visits
    End point description
    Data from Table 14.2-2.1 Appendix 16.2 CSR. Subjects analysed reported are considered at Baseline. Subjects analysed at 2 Weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 28 Placebo: 30 Subjects analysed at 4 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 29 Placebo: 30 Subjects analysed at 8 weeks: Pro-ocular 0.5%: 24 Pro-ocular 1%: 28 Placebo: 28
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 8
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: NEI scale score
    arithmetic mean (standard deviation)
        Baseline
    7.4 ( 3 )
    7.7 ( 2.88 )
    8.2 ( 3.47 )
        Week 2
    4.8 ( 3.51 )
    5.5 ( 3.88 )
    5.8 ( 2.98 )
        Week 4
    4.2 ( 2.02 )
    5.9 ( 3.19 )
    5.1 ( 3.10 )
        Week 8
    4.0 ( 2.82 )
    4.8 ( 3.08 )
    4.9 ( 3.98 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in Co
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 5
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in sum of Frequency and Intensity of Dryness/Irritation Patient Feeling assessed by SANDE questionnaire at Week 2, 4, 8, 16 (Day 14, 28, 56,114) as Intermediate Study Visits.

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in sum of Frequency and Intensity of Dryness/Irritation Patient Feeling assessed by SANDE questionnaire at Week 2, 4, 8, 16 (Day 14, 28, 56,114) as Intermediate Study Visits.
    End point description
    Data from Table 14.2-2.25 (Global Score) Appendix 16.2 CSR. Subjects analysed reported are considered at Baseline. Subjects analysed at 2 Weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 28 Placebo: 30 Subjects analysed at 4 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 28 Placebo: 30 Subjects analysed at 8 weeks: Pro-ocular 0.5%: 24 Pro-ocular 1%: 28 Placebo: 28 Subjects analysed at 16 weeks: Pro-ocular 0.5%: 24 Pro-ocular 1%: 27 Placebo: 25
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 8, 16
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: SANDE scale points
    arithmetic mean (standard deviation)
        Baseline
    70.2 ( 26.01 )
    63.9 ( 29.25 )
    74.7 ( 22.97 )
        Week 2
    60.5 ( 25.59 )
    58.9 ( 31.14 )
    58.7 ( 26.94 )
        Week 4
    56.0 ( 24.61 )
    52.3 ( 30.78 )
    52.2 ( 26.78 )
        Week 8
    49.1 ( 23.55 )
    56.0 ( 28.62 )
    48.0 ( 25.45 )
        Week 16
    43.8 ( 26.30 )
    43.1 ( 29.42 )
    36.7 ( 22.99 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in su
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 6
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in Conjunctival Fluorescein Staining assessed by NEI scale at Week 2, 4, 8 (Day 14, 28, 56) as Intermediate Study Visits

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in Conjunctival Fluorescein Staining assessed by NEI scale at Week 2, 4, 8 (Day 14, 28, 56) as Intermediate Study Visits
    End point description
    Data from Table 14.2-2.16 Appendix 16.2 CSR. Subjects analysed reported are considered at Baseline. Subjects analysed at 2 Weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 28 Placebo: 30 Subjects analysed at 4 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 29 Placebo: 30 Subjects analysed at 8 weeks: Pro-ocular 0.5%: 24 Pro-ocular 1%: 28 Placebo: 28
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 8
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: NEI scale score
    arithmetic mean (standard deviation)
        Nasal Total Baseline
    3.7 ( 2.89 )
    4.2 ( 2.70 )
    5.0 ( 3.27 )
        Nasal Total Week 2
    2.1 ( 2.32 )
    3.5 ( 2.53 )
    3.9 ( 3.32 )
        Nasal Total Week 4
    2.0 ( 2.23 )
    4.0 ( 2.84 )
    3.7 ( 3.07 )
        Nasal Total Week 8
    1.9 ( 2.54 )
    3.3 ( 2.49 )
    3.5 ( 3.49 )
        Temporal Total Baseline
    3.3 ( 3.15 )
    3.8 ( 2.62 )
    4.5 ( 3.22 )
        Temporal Total Week 2
    1.9 ( 2.34 )
    2.9 ( 2.46 )
    3.7 ( 3.16 )
        Temporal Total Week 4
    1.9 ( 2.21 )
    3.0 ( 2.54 )
    3.5 ( 3.17 )
        Temporal Total Week 8
    1.6 ( 2.48 )
    2.8 ( 2.47 )
    3.2 ( 3.36 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in Co
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 7
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in Non-Invasive Keratograph Tear Film Break-Up Time at each applicable Post-Baseline Visit (Week 2, 4, 8, 12 [Day 14, 28, 56, 84])

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in Non-Invasive Keratograph Tear Film Break-Up Time at each applicable Post-Baseline Visit (Week 2, 4, 8, 12 [Day 14, 28, 56, 84])
    End point description
    Data from Table 14.2-2.32 Appendix 16.2 CSR. Subjects analysed reported are considered at Baseline. Subjects analysed at 2 Weeks: Pro-ocular 0.5%: 25 Pro-ocular 1%: 27 Placebo: 30 Subjects analysed at 4 weeks: Pro-ocular 0.5%: 25 Pro-ocular 1%: 25 Placebo: 29 Subjects analysed at 8 weeks: Pro-ocular 0.5%: 21 Pro-ocular 1%: 24 Placebo: 28 Subjects analysed at 12 weeks: Pro-ocular 0.5%: 23 Pro-ocular 1%: 26 Placebo: 27
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 8, 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: second
    arithmetic mean (standard deviation)
        Baseline
    4.2 ( 1.96 )
    5.1 ( 3.26 )
    5.8 ( 4.76 )
        Week 2
    6.7 ( 3.76 )
    6.5 ( 4.07 )
    5.8 ( 3.14 )
        Week 4
    7.8 ( 4.73 )
    6.2 ( 4.70 )
    5.7 ( 3.35 )
        Week 8
    7.2 ( 3.95 )
    5.8 ( 3.56 )
    6.8 ( 4.41 )
        Week 12
    6.6 ( 3.53 )
    6.6 ( 4.70 )
    6.1 ( 3.81 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in No
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 8
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in Fluorescein Tear Film Break-Up Time at Week 12 (Day 84).

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in Fluorescein Tear Film Break-Up Time at Week 12 (Day 84).
    End point description
    Data from Table 14.2-2.39 Appendix 16.2 CSR. Subjects analysed reported are considered at 12 Weeks. Subjects analysed at Baseline: Pro-ocular 0.5%: 29 Pro-ocular 1%: 30 Placebo: 30
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    24
    28
    27
    Units: Seconds
    arithmetic mean (standard deviation)
        Baseline
    2.3 ( 0.61 )
    2.6 ( 1.12 )
    2.3 ( 1.02 )
        Week 12
    3.8 ( 2.55 )
    3.2 ( 2.78 )
    4.2 ( 2.76 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in Fl
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 9
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in Tear Meniscus Height at each applicable Post-Baseline Visit (Week 2, 4, 8, 12 [Day 14, 28, 56, 84])

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in Tear Meniscus Height at each applicable Post-Baseline Visit (Week 2, 4, 8, 12 [Day 14, 28, 56, 84])
    End point description
    Data from Table 14.2-2.46 Appendix 16.2 CSR. Subjects analysed reported are considered at Baseline. Subjects analysed at 2 Weeks: Pro-ocular 0.5%: 27 Pro-ocular 1%: 28 Placebo: 30 Subjects analysed at 4 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 28 Placebo: 29 Subjects analysed at 8 weeks: Pro-ocular 0.5%: 22 Pro-ocular 1%: 27 Placebo: 28 Subjects analysed at 12 weeks: Pro-ocular 0.5%: 25 Pro-ocular 1%: 28 Placebo: 27
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 8, 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: millimetre(s)
    arithmetic mean (standard deviation)
        Baseline
    1.0 ( 4.23 )
    0.3 ( 0.09 )
    0.3 ( 0.11 )
        Week 2
    0.3 ( 0.13 )
    0.2 ( 0.07 )
    0.3 ( 0.20 )
        Week 4
    1.1 ( 4.10 )
    0.3 ( 0.07 )
    0.3 ( 0.18 )
        Week 8
    0.3 ( 0.11 )
    0.3 ( 0.08 )
    0.3 ( 0.16 )
        Week 12
    0.3 ( 0.15 )
    0.3 ( 0.10 )
    0.3 ( 0.14 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in Te
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 10
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 0 Screening) in Schirmer’s Test at Week 4 (Day 28) and at Week 12 (Day 84).

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 0 Screening) in Schirmer’s Test at Week 4 (Day 28) and at Week 12 (Day 84).
    End point description
    Data from Table 32 CSR. Subjects analysed reported are considered at 12 Weeks. Subjects analysed at Baseline: Pro-ocular 0.5%: 29 Pro-ocular 1%: 30 Placebo: 30 Subjects analysed at 4 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 29 Placebo: 30
    End point type
    Secondary
    End point timeframe
    Week 4, 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    25
    28
    27
    Units: millimetre(s)
    arithmetic mean (standard deviation)
        Baseline
    3.2 ( 2.44 )
    3.6 ( 2.59 )
    2.9 ( 1.78 )
        Week 4
    4.3 ( 3.20 )
    2.9 ( 2.11 )
    5.6 ( 5.20 )
        Week 12
    6.8 ( 7.05 )
    4.6 ( 3.65 )
    5.9 ( 6.45 )
    Attachments
    		 Mean change from Baseline (Visit 0 Screening) in S
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 11
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1 [3]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - Van-Elteren test (Wilcoxon stratificato) se le assunzioni dell’ANCOVA non erano soddisfatte

    Secondary: Impact of dry eye on quality of life by using Dry Eye-Related Quality-of-Life Scale Questionnaire

    		 Close Top of page
    End point title
    		 Impact of dry eye on quality of life by using Dry Eye-Related Quality-of-Life Scale Questionnaire
    End point description
    Data from Table 34 CSR. Subjects analysed reported are considered at 12 Weeks. Subjects analysed at Baseline: Pro-ocular 0.5%: 29 Pro-ocular 1%: 30 Placebo: 30
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    24
    28
    27
    Units: Questionnaire score
    arithmetic mean (standard deviation)
        Baseline
    4.3 ( 1.11 )
    3.6 ( 1.25 )
    4.3 ( 1.15 )
        Week 12
    2.9 ( 0.95 )
    3.2 ( 1.03 )
    3.2 ( 0.89 )
    Attachments
    		 Impact of dry eye on quality of life by using Dry
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 12
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Absolute score of each symptom item in Visual Analogue Scale to each Post-Baseline Visit

    		 Close Top of page
    End point title
    		 Absolute score of each symptom item in Visual Analogue Scale to each Post-Baseline Visit
    End point description
    Data from Table 14.2-2.67 (Sum of all VAS) Appendix 16.2 CSR. Subjects analysed reported are considered at Baseline. Subjects analysed at 2 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 28 Placebo: 30 Subjects analysed at 4 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 28 Placebo: 30 Subjects analysed at 8 weeks: Pro-ocular 0.5%: 24 Pro-ocular 1%: 28 Placebo: 28 Subjects analysed at 12 weeks: Pro-ocular 0.5%: 25 Pro-ocular 1%: 28 Placebo: 27 Subjects analysed at 16 weeks: Pro-ocular 0.5%: 24 Pro-ocular 1%: 27 Placebo: 25
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 8, 12,16
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: VAS score
    arithmetic mean (standard deviation)
        Baseline
    399.9 ( 253.12 )
    339.7 ( 188.96 )
    459.8 ( 201.48 )
        Week 2
    282.5 ( 222.91 )
    301.2 ( 214.92 )
    324.7 ( 196.73 )
        Week 4
    290.1 ( 210.55 )
    288.4 ( 203.81 )
    282.2 ( 181.95 )
        Week 8
    257.1 ( 200.24 )
    308.2 ( 208.88 )
    269.9 ( 172.28 )
        Week 12
    248.8 ( 203.55 )
    256.1 ( 201.27 )
    225.9 ( 153.77 )
        Week 16
    220.8 ( 175.51 )
    259.1 ( 195.34 )
    217.9 ( 163.14 )
    Attachments
    		 Absolute score of each symptom item in Visual
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 13
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in Visual Analogue Scale 7 Symptoms items to each applicable Post-Baseline Visit (Week 2, 4, 8, 12 [Day 14, 28, 56, 84]).

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in Visual Analogue Scale 7 Symptoms items to each applicable Post-Baseline Visit (Week 2, 4, 8, 12 [Day 14, 28, 56, 84]).
    End point description
    Data from Table 14.2-2.67 (VAS mean) Appendix 16.2 CSR. Subjects analysed reported are considered at Baseline. Subjects analysed at 2 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 28 Placebo: 30 Subjects analysed at 4 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 28 Placebo: 30 Subjects analysed at 8 weeks: Pro-ocular 0.5%: 24 Pro-ocular 1%: 28 Placebo: 28 Subjects analysed at 12 weeks: Pro-ocular 0.5%: 25 Pro-ocular 1%: 28 Placebo: 27
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 8, 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: VAS scale score
    arithmetic mean (standard deviation)
        Baseline
    57.2 ( 33.54 )
    48.5 ( 27.03 )
    65.7 ( 28.89 )
        Week 2
    40.3 ( 31.89 )
    43.0 ( 30.71 )
    46.5 ( 28.12 )
        Week 4
    41.4 ( 29.97 )
    41.1 ( 29.16 )
    40.3 ( 26.00 )
        Week 8
    36.7 ( 28.58 )
    44.0 ( 29.79 )
    38.5 ( 24.58 )
        Week 12
    35.6 ( 29.04 )
    36.6 ( 28.68 )
    32.3 ( 22.02 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in Vi
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 14
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 1 pre-dose) in Corneal Sensitivity to each applicable Post-Baseline Visit (Week 4, 12 [Day 28, 84]).

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 1 pre-dose) in Corneal Sensitivity to each applicable Post-Baseline Visit (Week 4, 12 [Day 28, 84]).
    End point description
    Data from Table 14.2-2.74 Appendix 16.2 CSR. Subjects analysed reported are considered at Baseline. Subjects analysed at 4 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 29 Placebo: 30 Subjects analysed at 12 weeks: Pro-ocular 0.5%: 24 Pro-ocular 1%: 28 Placebo: 27
    End point type
    Secondary
    End point timeframe
    Week 4, 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: score
    arithmetic mean (standard deviation)
        Superior Nasal Baseline
    4.0 ( 2.57 )
    5.3 ( 1.46 )
    4.0 ( 2.36 )
        Superior Nasal Week 4
    4.1 ( 2.49 )
    5.4 ( 1.43 )
    4.1 ( 2.41 )
        Superior Nasal Week 12
    4.1 ( 2.55 )
    5.3 ( 1.52 )
    4.2 ( 2.43 )
        Inferior Nasal Baseline
    3.9 ( 2.53 )
    5.4 ( 1.46 )
    4.0 ( 2.34 )
        Inferior Nasal Week 4
    4.1 ( 2.51 )
    5.4 ( 1.45 )
    4.0 ( 2.39 )
        Inferior Nasal Week 12
    4.0 ( 2.49 )
    5.3 ( 1.53 )
    4.2 ( 2.43 )
        Superior Temporal Baseline
    4.0 ( 2.54 )
    5.3 ( 1.49 )
    3.9 ( 2.34 )
        Superior Temporal Week 4
    4.1 ( 2.49 )
    5.4 ( 1.46 )
    4.1 ( 2.41 )
        Superior Temporal Week 12
    4.1 ( 2.55 )
    5.3 ( 1.52 )
    4.2 ( 2.43 )
        Inferior Temporal Baseline
    4.0 ( 2.55 )
    5.4 ( 1.46 )
    3.9 ( 2.34 )
        Inferior Temporal Week 4
    4.1 ( 2.52 )
    5.4 ( 1.45 )
    4.0 ( 2.38 )
        Inferior Temporal Week 12
    4.0 ( 2.53 )
    5.3 ( 1.52 )
    4.2 ( 2.43 )
    Attachments
    		 Mean change from Baseline (Visit 1 pre-dose) in Co
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 15
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from Baseline (Visit 0 Screening) in Slit-Lamp Examination to each applicable Post-Baseline Visit (Week 2, 4, 8, 12 [Day 14, 28, 56, 84]).

    		 Close Top of page
    End point title
    		 Mean change from Baseline (Visit 0 Screening) in Slit-Lamp Examination to each applicable Post-Baseline Visit (Week 2, 4, 8, 12 [Day 14, 28, 56, 84]).
    End point description
    Data from Table 14.2-2.81 Appendix 16.2 CSR. For data spreadsheet, please refer to the attachment.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 8, 12 (Week 16 follow up included)
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    29
    30
    30
    Units: Subject number
    29
    30
    30
    Attachments
    		 Mean change from Baseline (Visit 0 Screening) in S
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 16
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Local and Systemic adverse events

    		 Close Top of page
    End point title
    		 Local and Systemic adverse events
    End point description
    Data from Table 54 CSR
    End point type
    Secondary
    End point timeframe
    Full trial duration
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    31
    30
    30
    Units: Number of events
        Local
    10
    6
    2
        Systemic
    13
    10
    6
    Attachments
    		 Local and Systemic adverse events
    No statistical analyses for this end point

    Secondary: Incidence and frequency of Treatment-emergent adverse events (TEAEs) at any time during the study.

    		 Close Top of page
    End point title
    		 Incidence and frequency of Treatment-emergent adverse events (TEAEs) at any time during the study.
    End point description
    Data from Table 55 CSR.
    End point type
    Secondary
    End point timeframe
    Full trial duration
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    31
    30
    30
    Units: Number of events
        Mild
    20
    13
    5
        Moderate
    2
    3
    1
        Severe
    1
    0
    1
    Attachments
    		 Incidence and frequency of Treatment-emergent adve
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 18
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Serum progesterone determination

    		 Close Top of page
    End point title
    		 Serum progesterone determination
    End point description
    Data from Table 59 CSR. In categories: NOR = normal AB NCS = abnormal Not Clinically Significant AB CS = abnormal Clinically Significant MIS = Missing
    End point type
    Secondary
    End point timeframe
    Pre-randomisation and Randomisation (RAN), Week 4 (W4), Week 12 (W12) and Early Termination (ET)
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    31
    30
    30
    Units: Number of patients
        RAN NOR
    30
    28
    30
        RAN AB NCS
    0
    1
    0
        RAN AB CS
    0
    0
    0
        RAN MIS
    1
    1
    0
        W4 NOR
    27
    24
    28
        W4 AB NCS
    0
    1
    1
        W4 AB CS
    0
    0
    0
        W4 MIS
    2
    4
    1
        W12 NOR
    23
    26
    26
        W12 AB NCS
    0
    2
    1
        W12 AB CS
    0
    0
    0
        W12 MIS
    3
    0
    0
        ET NOR
    0
    0
    0
        ET AB NCS
    0
    0
    0
        ET AB CS
    0
    0
    0
        ET MIS
    0
    0
    0
    Attachments
    		 Serum progesterone determination
    No statistical analyses for this end point

    Secondary: Mean change from baseline (Visit 1 pre-dose) in Intraocular Pressure at each applicable post-baseline visit [Week 2, 4, 8, 12 (Day 14, 28, 56, 84)].

    		 Close Top of page
    End point title
    		 Mean change from baseline (Visit 1 pre-dose) in Intraocular Pressure at each applicable post-baseline visit [Week 2, 4, 8, 12 (Day 14, 28, 56, 84)].
    End point description
    Data from Table 14.3.5-1.1 Appendix 16.2 CSR. Subjects analysed reported are considered at Baseline. Subjects analysed at 2 Weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 28 Placebo: 30 Subjects analysed at 4 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 29 Placebo: 30 Subjects analysed at 8 weeks: Pro-ocular 0.5%: 24 Pro-ocular 1%: 28 Placebo: 28 Subjects analysed at 12 weeks: Pro-ocular 0.5%: 25 Pro-ocular 1%: 28 Placebo: 27
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 8, 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    31
    30
    30
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline
    13.5 ( 2.20 )
    14.5 ( 1.81 )
    14.2 ( 1.97 )
        Week 2
    13.8 ( 1.40 )
    14.4 ( 1.64 )
    14.4 ( 2.30 )
        Week 4
    13.1 ( 1.74 )
    13.8 ( 1.94 )
    14.4 ( 1.35 )
        Week 8
    13.5 ( 1.53 )
    14.5 ( 1.93 )
    14.8 ( 3.01 )
        Week 12
    13.8 ( 1.41 )
    13.7 ( 2.03 )
    13.8 ( 1.93 )
    Attachments
    		 Mean change from baseline (Visit 1 pre-dose) in In
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 20
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from baseline (Visit 0 Screening) in Undilated Fundoscopy Examination at Week 12 (Day 84).

    		 Close Top of page
    End point title
    		 Mean change from baseline (Visit 0 Screening) in Undilated Fundoscopy Examination at Week 12 (Day 84).
    End point description
    Data from Table 14.3.5-1.3 In categories: N = Normal ANCS = Abnormal Not Clinically Significant ACS = Abnormal Clinically Significant M = Missing
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    31
    30
    30
    Units: Number of subjects
        Vitreous Week 12 N
    24
    28
    26
        Vitreous Week 12 ANCS
    0
    0
    1
        Vitreous Week 12 ACS
    0
    0
    0
        Vitreous Week 12 M
    2
    0
    0
        Retina/Macula Week 12 N
    24
    28
    26
        Retina/Macula Week 12 ANCS
    0
    0
    1
        Retina/Macula Week 12 ACS
    0
    0
    0
        Retina/Macula Week 12 M
    2
    0
    0
        Choroid Week 12 N
    24
    28
    26
        Choroid Week 12 ANCS
    0
    0
    1
        Choroid Week 12 ACS
    0
    0
    0
        Choroid Week 12 M
    2
    0
    0
        Optic Nerve Week 12 N
    24
    28
    26
        Optic Nerve Week 12 ANCS
    0
    0
    1
        Optic Nerve Week 12 ACS
    0
    0
    0
        Optic Nerve Week 12 M
    2
    0
    0
        Cup/Disc Ratio Week 12 N
    24
    27
    26
        Cup/Disc Ratio Week 12 ANCS
    0
    0
    1
        Cup/Disc Ratio Week 12 ACS
    0
    1
    0
        Cup/Disc Ratio Week 12 M
    2
    0
    0
    Attachments
    		 Mean change from baseline (Visit 0 Screening) in U
    No statistical analyses for this end point

    Secondary: Mean change from baseline (Visit 1 pre-dose) in BCVA at each applicable post- baseline visit [Week 2, 4, 8, 12 (Day 14, 28, 56, 84)].

    		 Close Top of page
    End point title
    		 Mean change from baseline (Visit 1 pre-dose) in BCVA at each applicable post- baseline visit [Week 2, 4, 8, 12 (Day 14, 28, 56, 84)].
    End point description
    Data from Table 14.3.5-1.5 Subjects analysed reported are considered at Baseline. Subjects analysed at 2 Weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 28 Placebo: 30 Subjects analysed at 4 weeks: Pro-ocular 0.5%: 28 Pro-ocular 1%: 29 Placebo: 30 Subjects analysed at 8 weeks: Pro-ocular 0.5%: 24 Pro-ocular 1%: 28 Placebo: 28 Subjects analysed at 8 weeks: Pro-ocular 0.5%: 24 Pro-ocular 1%: 28 Placebo: 27
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 8, 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    31
    30
    30
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    0.07 ( 0.122 )
    0.04 ( 0.122 )
    0.03 ( 0.096 )
        Week 2
    0.08 ( 0.129 )
    -0.54 ( 3.035 )
    0.03 ( 0.095 )
        Week 4
    0.07 ( 0.106 )
    0.04 ( 0.126 )
    0.02 ( 0.095 )
        Week 8
    0.09 ( 0.161 )
    0.06 ( 0.145 )
    0.02 ( 0.101 )
        Week 12
    0.06 ( 0.113 )
    0.06 ( 0.136 )
    0.04 ( 0.151 )
    Attachments
    		 Mean change from baseline (Visit 1 pre-dose) in BC
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 22
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from baseline (Visit 0 Screening) in Meiboscore grading at Week 12 (Day 84).

    		 Close Top of page
    End point title
    		 Mean change from baseline (Visit 0 Screening) in Meiboscore grading at Week 12 (Day 84).
    End point description
    Data from Table 67 CSR. 0 = No loss of meibomian glands 1 = Loss of less than 1/3 of the total meibomian gland area 2 = Loss of 1/3 to 2/3 of the total area 3 = Loss of more than 2/3 of the area
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    31
    30
    30
    Units: Score of Meiboscore Grading
        Screening 0
    6
    13
    6
        Screening 1
    8
    6
    3
        Screening 2
    13
    9
    15
        Screening 3
    4
    2
    6
        Week 12 0
    6
    11
    4
        Week 12 1
    11
    11
    7
        Week 12 2
    5
    6
    14
        Week 12 3
    2
    0
    2
        Missing
    2
    0
    0
    Attachments
    		 Mean change from baseline (Visit 0 Screening) in M
    Statistical analysis title
    		 Statistical analysis secondary endpoint n. 23
    Comparison groups
    Pro-ocular™ 0.5% v Pro-ocular™ 1% v Placebo
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from baseline (Visit 1 pre-dose) in (Keratography) Conjunctival Hyperemia score to each applicable post-baseline visit [Week 2, 4, 8, 12 (Day 14, 28, 56, 84)].

    		 Close Top of page
    End point title
    		 Mean change from baseline (Visit 1 pre-dose) in (Keratography) Conjunctival Hyperemia score to each applicable post-baseline visit [Week 2, 4, 8, 12 (Day 14, 28, 56, 84)].
    End point description
    0 = None 1 = Mild 2 = Moderate 3 = Severe Missing
    End point type
    Secondary
    End point timeframe
    Data from Table 69 CSR. Randomisation, pre-randomisation Randomisation, post-randomisation Week 2 Week 4 Week 8 Week 12
    End point values
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Number of subjects analysed
    31
    30
    30
    Units: Number of patients
        Randomisation, pre-randomisation 0
    0
    0
    1
        Randomisation, pre-randomisation 1
    13
    11
    11
        Randomisation, pre-randomisation 2
    14
    15
    16
        Randomisation, pre-randomisation 3
    4
    3
    1
        Randomisation, pre-randomisation Missing
    0
    0
    1
        Randomisation, post-randomisation 0
    0
    0
    1
        Randomisation, post-randomisation 1
    15
    13
    13
        Randomisation, post-randomisation 2
    10
    13
    13
        Randomisation, post-randomisation 3
    5
    2
    1
        Randomisation, post-randomisation Missing
    1
    0
    2
        Week 2 0
    0
    0
    1
        Week 2 1
    15
    13
    18
        Week 2 2
    9
    12
    11
        Week 2 3
    3
    3
    0
        Week 2 Missing
    2
    0
    0
        Week 4 0
    0
    0
    0
        Week 4 1
    12
    12
    16
        Week 4 2
    14
    14
    11
        Week 4 3
    1
    2
    2
        Week 4 Missing
    1
    1
    1
        Week 8 0
    0
    0
    1
        Week 8 1
    11
    10
    13
        Week 8 2
    10
    12
    13
        Week 8 3
    1
    4
    1
        Week 8 Missing
    5
    2
    0
        Week 12 0
    0
    0
    0
        Week 12 1
    14
    13
    12
        Week 12 2
    7
    10
    13
        Week 12 3
    2
    4
    2
        Week 12 Missing
    2
    0
    0
    Attachments
    		 Mean change from baseline (Visit 1 pre-dose) in (K
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    The safety evaluation will cover the collection of adverse events since the signature of the Informed Consent Form by each patient to the end of the study and follow up.
    Adverse event reporting additional description
    All non-serious adverse events were reported regardless of frequency.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Pro-ocular™ 0.5%
    Reporting group description
    		 Pro-ocular™ 0.5% topical gel (0.35 mg progesterone/dose, BID to forehead for 12 weeks) was tested in adults with moderate to severe dry eye.

    Reporting group title
    Pro-ocular™ 1%
    Reporting group description
    		 Pro-ocular™ 1% topical gel (0.7 mg progesterone/dose, BID to forehead for 12 weeks) was tested in adults with moderate to severe dry eye.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo topical gel (no active ingredient; titanium dioxide instead of progesterone), identical in appearance and dosing to active gel (0.07g BID to forehead for 12 weeks).

    Serious adverse events
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Pro-ocular™ 0.5% Pro-ocular™ 1% Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 31 (41.94%)
    8 / 30 (26.67%)
    6 / 30 (20.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    3
    Eye disorders
    Ocular discomfort
         subjects affected / exposed
    13 / 31 (41.94%)
    8 / 30 (26.67%)
    6 / 30 (20.00%)
         occurrences all number
    22
    16
    8

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Sep 2021
    The most substantial change between Version 1.0 (July 2019) and Version 2.0 (September 2021) involves the addition of exploratory objectives and endpoints. Version 2.0 introduces a combined eye analysis examining both eyes simultaneously, rather than focusing solely on the "worst eye." Furthermore, direct comparisons between the two progesterone concentrations (0.5% vs 1.0%) were added as exploratory endpoints. To accommodate the combined eye analysis, Version 2.0 incorporates a Mixed Model Repeated Measures (MMRM) approach, which accounts for within-subject correlation between both eyes. Moreover, TearScan Grading was completely removed from the assessment schedule, eliminating associated procedures from all study visits. Finally, the study timeline was delayed, with the start moved from Q4 2019 to Q1 2021, and expected completion shifted from Q2 2020 to Q1 2022. Reflecting updated regulatory requirements, Version 2.0 includes references to EU Regulation 536/2014 regarding document retention requirements. In summary, the amendment maintains all primary and secondary objectives unchanged while substantially enriching the exploratory research potential through bilateral eye analysis and direct dose comparison.

    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.
    Study was interrupted at 91 randomized patients, due to a very slow and difficult recruitment lower dropout rate than planned. Even with 91 randomized, the power was 80% so fully acceptable from a statistical point of view.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Fri Jan 09 16:47:17 CET 2026 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA