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    Clinical Trial Results:
    A double-masked study of SYL1001 in patients with moderate to severe dry eye disease (DED)

    Summary
    EudraCT number
    2016-003903-79
    Trial protocol
    DE   ES   PT   EE   SK   IT  
    Global end of trial date
    16 Nov 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Dec 2019
    First version publication date
    02 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SYL1001_IV
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sylentis SAU – Pharma Mar Group
    Sponsor organisation address
    Parque Tecnológico de Madrid C/Santiago Grisolía nº 2 Tres Cantos 28760, Madrid, Spain,
    Public contact
    Regulatory Affairs, Sylentis SAU, +34 91806 31 88, vruz@sylentis.com
    Scientific contact
    Regulatory Affairs, Sylentis SAU, +34 91806 31 88, vruz@sylentis.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
    16 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objectives: 1. Change from Baseline in Visual Analogue Scale (VAS) scores for eye discomfort/pain after 28 days of treatment. 2. Change from Baseline in Corneal Fluorescein Staining (CFS) total scores obtained on the Oxford scale after 28 days of treatment. 3. Change from Baseline in conjunctival hyperemia scores based on the McMonnies scale after 28 days of treatment.
    Protection of trial subjects
    This study was conducted in accordance with the protocol, the ICH guidelines and guidelines for Good Clinical Practice (GCP), with the Declaration of Helsinki (revised version, Fortaleza, October 2013) and the local laws and guidelines of the countries in which the study was conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 May 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
    Portugal: 4
    Country: Number of subjects enrolled
    Slovakia: 47
    Country: Number of subjects enrolled
    Spain: 105
    Country: Number of subjects enrolled
    Estonia: 69
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Italy: 28
    Worldwide total number of subjects
    289
    EEA total number of subjects
    289
    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)
    186
    From 65 to 84 years
    103
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, 289 patients, 143 in the SYL1001 and 146 in the vehicle group were randomized and received treatment at 15 clinical sites in Spain, 2 clinical sites in Portugal, 8 clinical sites in Germany, 3 clinical sites in Estonia, 4 clinical sites in Italy and 7 clinical sites in Slovakia.

    Pre-assignment
    Screening details
    Once suitability for the study was verified, patients entered a 7-day run-in period. They self-administrated the vehicle ophthalmic solution once a day at 09:00am ± 1 hour. During the run-in period, patients noted all instillation times into a diary. Administration of artificial tears at least ± 1 hour from vehicle administration, max 4 drops/day

    Pre-assignment period milestones
    Number of subjects started
    289
    Number of subjects completed
    289

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer
    Blinding implementation details
    A computer-generated randomization schedule using a block design was used to assign subjects to the two treatment arms. The vehicle and SYL1001 ophthalmic solution were supplied in a way in that they were indistinguishable from each other, in order to maintain the masking of the clinical trial. The Sponsor provided a kit containing the single-dose plastic containers of the assigned treatment for each patient. Neither the research team or patient knew which treatment they had been assigned.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SYL1001
    Arm description
    11.25 mg/mL SYL1001 ophthalmic solution, one drop per eye per day for 28 consecutive days
    Arm type
    Experimental

    Investigational medicinal product name
    Tivanisiran
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    11.25 mg/mL, one drop per eye per day for 28 consecutive days

    Arm title
    Vehicle Solution
    Arm description
    Buffer saline solution 0.97%, one drop per eye each day for 28 consecutive days
    Arm type
    Placebo

    Investigational medicinal product name
    buffer saline solution 0.97%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    One drop per eye each day for 28 consecutive days

    Number of subjects in period 1
    SYL1001 Vehicle Solution
    Started
    143
    146
    Completed
    132
    139
    Not completed
    11
    7
         Protocol deviation
    3
    3
         At specific request of the sponsor
    1
    1
         Onset of any non-inclusion criteria
    1
    -
         Intercurrent disease or intolerable AE
    2
    2
         Compliance less than indicated in the protocol
    4
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SYL1001
    Reporting group description
    11.25 mg/mL SYL1001 ophthalmic solution, one drop per eye per day for 28 consecutive days

    Reporting group title
    Vehicle Solution
    Reporting group description
    Buffer saline solution 0.97%, one drop per eye each day for 28 consecutive days

    Reporting group values
    SYL1001 Vehicle Solution Total
    Number of subjects
    143 146 289
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    90 96 186
        From 65-84 years
    53 50 103
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    118 125 243
        Male
    25 21 46
    Ethnic Group
    Units: Subjects
        Asian
    0 0 0
        Black
    0 1 1
        Caucasian
    125 122 247
        Other
    0 4 4
        Not provided as per local laws
    18 19 37

    End points

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    End points reporting groups
    Reporting group title
    SYL1001
    Reporting group description
    11.25 mg/mL SYL1001 ophthalmic solution, one drop per eye per day for 28 consecutive days

    Reporting group title
    Vehicle Solution
    Reporting group description
    Buffer saline solution 0.97%, one drop per eye each day for 28 consecutive days

    Primary: Primary efficacy endpoint: Score for eye discomfort/pain

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    End point title
    Primary efficacy endpoint: Score for eye discomfort/pain
    End point description
    Change from Baseline in Visual Analogue Scale (VAS) score for eye discomfort/pain after 28 days of treatment, which was defined as VAS at analysis visit 3 – VAS at Baseline. Eye discomfort/pain was analyzed from the scores recorded in the eCRF by the investigator. This score represents the distance (mm) from 0 in the corresponding eye discomfort/pain visual analogue scale and ranges from 0 to 100. Higher scores in the VAS described worst severity.
    End point type
    Primary
    End point timeframe
    Baseline and Day 28
    End point values
    SYL1001 Vehicle Solution
    Number of subjects analysed
    143
    146
    Units: unit(s)
    arithmetic mean (standard deviation)
        Absolute change from baseline number
    -16.10 ± 21.31
    -16.58 ± 21.62
    Statistical analysis title
    Statistical analysis 1 for Clinical Efficacy
    Statistical analysis description
    Change from Baseline in Visual Analogue Scale (VAS) score for eye discomfort/pain after 28 days of treatment.
    Comparison groups
    SYL1001 v Vehicle Solution
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.926
    Method
    ANCOVA
    Confidence interval

    Primary: Primary efficacy endpoint: Corneal Fluorescein Staining

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    End point title
    Primary efficacy endpoint: Corneal Fluorescein Staining
    End point description
    Change from Baseline in Corneal Fluorescein Staining (CFS) after 28 days of treatment. The Oxford scale ranges from 0 to 5 (0 = no staining, 5= severe) with 0.5 points increments. The eye was divided into five zones: central, nasal, temporal, superior and inferior. Each zone was scored separately and recorded in the CRF. The Total score CFS obtained on the Oxford scale was defined as the sum of the five zones scores (0 to 25). Change was calculated as the CFS at analysis visit 3 – CFS at Baseline. Higher scores in the Oxford scale described worst severity.
    End point type
    Primary
    End point timeframe
    Baseline and Day 28
    End point values
    SYL1001 Vehicle Solution
    Number of subjects analysed
    143
    146
    Units: unit(s)
    arithmetic mean (standard deviation)
        Absolute change from baseline number
    -2.37 ± 2.97
    -1.71 ± 3.00
    Statistical analysis title
    Statistical analysis 2 for Clinical Efficacy
    Statistical analysis description
    Change from Baseline in Corneal Fluorescein Staining (CFS) after 28 days of treatment
    Comparison groups
    SYL1001 v Vehicle Solution
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.208
    Method
    ANCOVA
    Confidence interval

    Primary: Primary efficacy endpoint: Conjunctival hyperemia score

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    End point title
    Primary efficacy endpoint: Conjunctival hyperemia score
    End point description
    Change from Baseline in conjunctival hyperemia score based on the McMonnies scale after 28 days of treatment, which was defined as McMonnies at analysis visit 3 - McMonnies at Baseline. The McMonnies scale ranges from 0 to 5. Conjunctival hyperemia was analysed from the scores recorded in the eCRF by the investigator. Higher scores in the McMonnies scale described worst severity.
    End point type
    Primary
    End point timeframe
    Baseline and Day 28
    End point values
    SYL1001 Vehicle Solution
    Number of subjects analysed
    143
    146
    Units: unit(s)
    arithmetic mean (standard deviation)
        Absolute change from baseline number
    -0.51 ± 0.88
    -0.44 ± 0.90
    Statistical analysis title
    Statistical analysis 3 for Clinical Efficacy
    Statistical analysis description
    Change from Baseline in conjunctival hyperemia score based on the McMonnies scale after 28 days of treatment
    Comparison groups
    SYL1001 v Vehicle Solution
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.451
    Method
    ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    28 days
    Adverse event reporting additional description
    5 patients had serious non-ocular AEs reported, 1 in the SYL1001 group & 4 in the vehicle group; none was related to treatment. 9 patients had 13 treatment related ocular AEs, 6 in the SYL1001 group had 8 related ocular AEs and 3 in the vehicle groups had 5 related ocular AE's. 1 patient in the SYL1001 group reported 1 related non-ocular AE.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    SYL1001
    Reporting group description
    11.25 mg/mL SYL1001 ophthalmic solution, one drop per eye per day for 28 consecutive days

    Reporting group title
    Vehicle Solution
    Reporting group description
    Buffer saline solution 0.97%, one drop per eye each day for 28 consecutive days

    Serious adverse events
    SYL1001 Vehicle Solution
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 143 (0.70%)
    4 / 146 (2.74%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    SYL1001 Vehicle Solution
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 143 (25.87%)
    39 / 146 (26.71%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Cyst removal
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 143 (1.40%)
    1 / 146 (0.68%)
         occurrences all number
    2
    1
    Injury, poisoning and procedural complications
    Eye burns
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Head injury
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Snake bite
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Blood creatine increased
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Platelet count abnormal
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Scan myocardial perfusion
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    2
    Congenital, familial and genetic disorders
    Distichiasis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 146 (0.68%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 143 (2.10%)
    2 / 146 (1.37%)
         occurrences all number
    5
    2
    Dizziness
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 146 (0.68%)
         occurrences all number
    1
    1
    Migraine
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Eye disorders
    Eye irritation
         subjects affected / exposed
    3 / 143 (2.10%)
    2 / 146 (1.37%)
         occurrences all number
    3
    3
    Photophobia
         subjects affected / exposed
    2 / 143 (1.40%)
    0 / 146 (0.00%)
         occurrences all number
    2
    0
    Blepharitis allergic
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Eye pruritus
         subjects affected / exposed
    3 / 143 (2.10%)
    0 / 146 (0.00%)
         occurrences all number
    5
    0
    Eye pain
         subjects affected / exposed
    2 / 143 (1.40%)
    4 / 146 (2.74%)
         occurrences all number
    2
    4
    Vision blurred
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Dry eye
         subjects affected / exposed
    3 / 143 (2.10%)
    1 / 146 (0.68%)
         occurrences all number
    4
    1
    Ocular toxicity
         subjects affected / exposed
    2 / 143 (1.40%)
    0 / 146 (0.00%)
         occurrences all number
    2
    0
    Blindness
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Eyelids pruritus
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Chalazion
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Corneal erosion
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    2
    Ectropion
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Eyelid cyst
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Foreign body sensation in eyes
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Ocular discomfort
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Punctate keratitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Odynophagia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Renal colic
         subjects affected / exposed
    0 / 143 (0.00%)
    2 / 146 (1.37%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Joint effusion
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Arthralgia
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 143 (2.10%)
    4 / 146 (2.74%)
         occurrences all number
    3
    4
    Influenza
         subjects affected / exposed
    1 / 143 (0.70%)
    2 / 146 (1.37%)
         occurrences all number
    1
    2
    Pneumonia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    2
    Pharyngitis
         subjects affected / exposed
    0 / 143 (0.00%)
    2 / 146 (1.37%)
         occurrences all number
    0
    2
    Tooth infection
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jun 2017
    Addition of a Clinical Global Impression Questionnaire for both patient and Clinician at Day 28. Addition of Impression Cytology procedure at Day 0 and Day 28. Update of the inclusion criterion #10 Previous wording: “Corrected visual acuity ≥0.7 logMAR (20/100 Snellen or 50 ETDRS) in both eyes”. New wording: “Corrected visual acuity ≤ 0.7 logMAR (≥20/100 Snellen or ≥50 ETDRS) in both eyes” Update of the paragraph related to inclusion criteria for VAS. Previous wording: “Assessment of inclusion/non-inclusion criteria will be performed both at the Screening Visit (V0) and at the Baseline visit (V1). All inclusion criteria must be met in the eye with the highest VAS scoring. VAS must be ≥ 20 for the fellow eye. The eye with the highest VAS scoring at the Screening Visit (V0) is not necessarily the same eye with the highest VAS scoring at the Baseline Visit. […]” New wording: “Assessment of inclusion/non-inclusion criteria will be performed both at the Screening Visit (V0) and at the Baseline visit (V1). Since the allocated treatment will be administered in both eyes, a minimum level of 20 in the VAS scale for pain/discomfort is required in the two eyes. All inclusion criteria must be met in the eye with the highest VAS scoring. VAS must be ≥ 20 for the fellow eye. The eye with the highest VAS scoring at the Screening Visit (V0) is not necessarily the same eye with the highest VAS scoring at the Baseline Visit. […]” Update of the non-inclusion criterion #2 Previous wording: “[…] and documented use of condoms”. New wording: “[…] and documented use of condoms” Update of the non-inclusion criterion #9 Previous wording: “Use of contact lenses or punctual plugs during the treatment and the previous 7 days (prior to treatment initiation).” New wording: “Use of contact lenses or presence of punctual plugs during the treatment and the previous 7 days (prior to treatment initiation).”
    06 Jun 2017
    Update of the non-inclusion criterion #11 Previous wording: “Previous refractive surgery, cornea transplant. Meibomian gland dysfunction or history of lid malposition (ectropion, entropion, ptosis), that may affect accurate assessment of the disease and/or mask the effects of the drug New wording: “ Previous refractive surgery, cornea transplant. Meibomian gland dysfunction or history of lid malposition (ectropion, entropion, ptosis), history of recurrent corneal herpes or history of recurrent corneal erosion or neurotrophic keratopathy that may affect accurate assessment of the disease and/or mask the effects of the drug” Paragraph 5.2. Randomization is more consistent: “Patients who meet all of the inclusion and none of the non-inclusion criteria at the Baseline visit will be randomized. Treatments will be allocated following a pre-established randomization list using a random design by blocks created by Linical Co. Ltd. The team ins charge of the randomization is located at a separate office from the main reporting team in order to preserve the masking of the investigational product. Numbers will consist of 5-digit identifiers which will act as both Subject Randomization Number and Medication Identifier. Drug packaging (Idifarma) will apply these 5-digit identifiers to the vials containing the investigational products. Once the investigator has confirmed that a subject is eligible for randomization, the eCRF will assign the next randomization number available at the site and this number medication will be used throughout the entire treatment period.
    06 Jun 2017
    Drug packaging will retain a list of the mapping of 5-digit identifiers to investigational product which will be supplied to the reporting statistician only at the time of full study unmasking, post database lock, in order to determine the medication actually received. The information on this list will also be provided to the designated research personnel of each site in a sealed, tamper-proof format such that emergency unmasking of the contents of a single vial only can be performed if required.” Update of protocol titles 4.1 and 4.2. Previous wording: “4.1. Primary outcomes” & “4.2. Secondary outcomes” New wording: “4.1. Primary outcomes/objectives”& “4.2. Secondary outcomes/objectives” 7.4.1 Labelling distribution and storage Name of manufacturer of artificial tears was changed from “Theradis” to “Idifarma” 8.1 Detailed Study Plan The order of procedures has been updated 8.3.3 Ocular tests – IOP Previous wording: “The IOP measurement will be performed in both eyes between 9 a.m. and 12 p.m by contact tonometry.” New wording: “The IOP measurement will be performed in both eyes at the same time (± 1 h) at every visit between 9 a.m. and 12 p.m. by contact tonometry.” 10.2.8 Notifications of AEs Update of the email address to be used for notifications of AEs 12.4 Confidentiality of data; 14.1 Source documents; 14.3 Monitoring In these sections, addition that the direct access to the data by Monitors (access direct conditioned to the compliance of certain rules) and by Regulatory Authorities as well as Ethics Committee remains through the investigator

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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