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    Clinical Trial Results:
    A Multicenter, Double-masked, Randomized Study to Compare the Safety and Efficacy of an Investigational Eye Drop Formulation with OPTIVE™ Unit-Dose for 3 Months in Subjects with Dry Eye Disease

    Summary
    EudraCT number
    2012-002238-35
    Trial protocol
    GB   BE   DE   IT   ES  
    Global end of trial date
    23 May 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Mar 2016
    First version publication date
    30 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    11002X-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01664949
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Allergan Limited
    Sponsor organisation address
    Allergan Limited Marlow International The Parkway, Marlow, United Kingdom,
    Public contact
    Allergan Limited EU Regulatory Dept, Allergan Limited, +44 1628 494444, ml-eu_reg_affairs@allergan.com
    Scientific contact
    Allergan Limited EU Regulatory Dept, Allergan Limited, +44 1628 494444, ml-eu_reg_affairs@allergan.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
    08 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study evaluated the safety and efficacy of a carboxymethylcellulose based eye drop formulation compared with carboxymethylcellulose based preservative-free lubricant eye drops [OPTIVE Unit-dose (UD)] in subjects with dry eye disease.
    Protection of trial subjects
    All participants were required to read and sign an informed consent form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Feb 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 112
    Country: Number of subjects enrolled
    Belgium: 27
    Country: Number of subjects enrolled
    France: 40
    Country: Number of subjects enrolled
    Germany: 86
    Country: Number of subjects enrolled
    Italy: 53
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Spain: 82
    Country: Number of subjects enrolled
    United Kingdom: 30
    Worldwide total number of subjects
    460
    EEA total number of subjects
    318
    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)
    297
    From 65 to 84 years
    159
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants with signs and symptoms of dry eye disease were enrolled in one of 2 treatment groups: Carboxymethylcellulose Based Eye Drop Formulation A or OPTIVE Unit-dose (UD).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Carer, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Carboxymethylcellulose Based Eye Drop Formulation A
    Arm description
    Carboxymethylcellulose Based Eye Drop Formulation A 1-2 drops in each eye as needed at least 2 times daily for 90 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Carboxymethylcellulose Based Eye Drop Formulation A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution in single-dose container
    Routes of administration
    Ocular use
    Dosage and administration details
    1 to 2 drops in each eye as needed, at least twice daily

    Arm title
    OPTIVE UD
    Arm description
    Carboxymethylcellulose Based Preservative-Free Lubricant Eye Drops (OPTIVE UD) 1-2 drops in each eye as needed at least 2 times daily for 90 days.
    Arm type
    Active comparator

    Investigational medicinal product name
    OPTIVE UD
    Investigational medicinal product code
    Other name
    OPTAVA™, OPTIVE™
    Pharmaceutical forms
    Eye drops, solution in single-dose container
    Routes of administration
    Ocular use
    Dosage and administration details
    1 to 2 drops in each eye as needed, at least twice daily

    Number of subjects in period 1
    Carboxymethylcellulose Based Eye Drop Formulation A OPTIVE UD
    Started
    224
    236
    Completed
    200
    211
    Not completed
    24
    25
         Protocol deviation
    5
    5
         Lack of efficacy
    1
    1
         Other Miscellaneous Reasons
    3
    1
         Personal Reasons
    3
    4
         Adverse event, non-fatal
    11
    12
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Carboxymethylcellulose Based Eye Drop Formulation A
    Reporting group description
    Carboxymethylcellulose Based Eye Drop Formulation A 1-2 drops in each eye as needed at least 2 times daily for 90 days.

    Reporting group title
    OPTIVE UD
    Reporting group description
    Carboxymethylcellulose Based Preservative-Free Lubricant Eye Drops (OPTIVE UD) 1-2 drops in each eye as needed at least 2 times daily for 90 days.

    Reporting group values
    Carboxymethylcellulose Based Eye Drop Formulation A OPTIVE UD Total
    Number of subjects
    224 236 460
    Age categorical
    Units: Subjects
        < 30 years
    9 10 19
        30 to 40 years
    15 15 30
        > 40 years
    200 211 411
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.6 ± 13.77 57.6 ± 13.65 -
    Gender, Male/Female
    Units: Participants
        Female
    182 189 371
        Male
    42 47 89

    End points

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    End points reporting groups
    Reporting group title
    Carboxymethylcellulose Based Eye Drop Formulation A
    Reporting group description
    Carboxymethylcellulose Based Eye Drop Formulation A 1-2 drops in each eye as needed at least 2 times daily for 90 days.

    Reporting group title
    OPTIVE UD
    Reporting group description
    Carboxymethylcellulose Based Preservative-Free Lubricant Eye Drops (OPTIVE UD) 1-2 drops in each eye as needed at least 2 times daily for 90 days.

    Primary: Change from Baseline in Ocular Surface Disease Index (OSDI) Score at Day 90

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    End point title
    Change from Baseline in Ocular Surface Disease Index (OSDI) Score at Day 90 [1]
    End point description
    The OSDI consists of 12 questions to assess visual function, ocular symptoms and environmental triggers related to dry eye. Each of the 12 questions is assessed using a 5-point scale (0=none of the time; 4 = all of the time) which is converted to a total score between 0-100. OSDI total scores of 0-12=normal (best), 13-22= mild ocular surface disease, 23-32 =moderate ocular surface disease, and 33-100=severe ocular surface disease (worst). A negative number change from Baseline indicates improvement.
    End point type
    Primary
    End point timeframe
    Baseline, Day 90
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical Analysis is reported for this outcome measure
    End point values
    Carboxymethylcellulose Based Eye Drop Formulation A OPTIVE UD
    Number of subjects analysed
    196
    198
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=196,198)
    41.77 ± 14.018
    40.92 ± 13.31
        Change from Baseline at Day 90 (n=181,185)
    -16.88 ± 17.496
    -15.97 ± 16.146
    No statistical analyses for this end point

    Secondary: Change from Baseline in Tear Break-up Time (TBUT)

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    End point title
    Change from Baseline in Tear Break-up Time (TBUT)
    End point description
    TBUT is the time in seconds for the tear film to visually break up after a complete blink. The average of 3 consecutive observations is reported for each participant. The longer it takes, the more stable the tear film. The eye with the shorter average TBUT at Baseline was used for analysis. A positive number change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 90
    End point values
    Carboxymethylcellulose Based Eye Drop Formulation A OPTIVE UD
    Number of subjects analysed
    196
    198
    Units: seconds
    arithmetic mean (standard deviation)
        Baseline (n=196,198)
    4.5 ± 1.868
    4.44 ± 1.894
        Change from Baseline at Day 90 (n=181,185)
    2.69 ± 5.167
    2.24 ± 3.262
    No statistical analyses for this end point

    Secondary: Change from Baseline in Corneal Staining

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    End point title
    Change from Baseline in Corneal Staining
    End point description
    Staining of the cornea following ocular administration of fluorescein dye was graded using a 6-point scale (0=no staining, 5=diffuse staining). The eye with the higher score at Baseline was used for analysis. The higher the grade score, the worse the dry eye severity. A negative number change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 90
    End point values
    Carboxymethylcellulose Based Eye Drop Formulation A OPTIVE UD
    Number of subjects analysed
    196
    198
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=196,198)
    1.5 ± 0.99
    1.6 ± 0.99
        Change from Baseline at Day 90 (n= 182, 184)
    -0.7 ± 0.88
    -0.9 ± 0.91
    No statistical analyses for this end point

    Secondary: Change from Baseline in Conjunctival Staining

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    End point title
    Change from Baseline in Conjunctival Staining
    End point description
    Staining of the conjunctiva following ocular administration of lissamine green dye was graded using a 6-point scale (0=no staining, 5=diffuse staining). Conjunctival staining has 2 zones, nasal and temporal, which are added together to provide the total staining score. The eye with the higher score at Baseline was used for analysis. The higher the grade score, the worse the dry eye severity. A negative number change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 90
    End point values
    Carboxymethylcellulose Based Eye Drop Formulation A OPTIVE UD
    Number of subjects analysed
    196
    198
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=196,198)
    2.8 ± 1.7
    3 ± 1.79
        Change from Baseline at Day 90 (n= 181, 185)
    -1.3 ± 1.57
    -1.4 ± 1.59
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Schirmer Test

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    End point title
    Change from Baseline in the Schirmer Test
    End point description
    The Schirmer's Test measures the rate of the secretion of tears produced by the eye over 5 minutes. The results indicate the presence of dry eye. The eye with the lower value at Baseline was used for Analysis. Normal = greater than or equal to 15 millimeters (mm) of tears, Dry Eye = less than 15 mm of tears. The smaller the number, the more severe the dry eye. A positive number change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 90
    End point values
    Carboxymethylcellulose Based Eye Drop Formulation A OPTIVE UD
    Number of subjects analysed
    196
    198
    Units: mm/5 minutes
    arithmetic mean (standard deviation)
        Baseline (n=196,198)
    9.29 ± 6.692
    8.1 ± 5.888
        Change from Baseline at Day 90 (n=172,174)
    1.38 ± 6.933
    1.53 ± 6.253
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 90 Days
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    OPTIVE UD
    Reporting group description
    Carboxymethylcellulose Based Preservative-Free Lubricant Eye Drops (OPTIVE UD) 1-2 drops in each eye as needed at least 2 times daily for 90 days.

    Reporting group title
    Carboxymethylcellulose Based Eye Drop Formulation A
    Reporting group description
    Carboxymethylcellulose Based Eye Drop Formulation A 1-2 drops in each eye as needed at least 2 times daily for 90 days.

    Serious adverse events
    OPTIVE UD Carboxymethylcellulose Based Eye Drop Formulation A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 236 (1.69%)
    5 / 224 (2.23%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Vitello-intestinal duct remnant
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anti-neutrophil cytoplasmic antibody positive vasculitis
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety disorder
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
    Additional description: Adverse Event male specific.
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis acute
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 224 (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: 5%
    Non-serious adverse events
    OPTIVE UD Carboxymethylcellulose Based Eye Drop Formulation A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 236 (2.54%)
    15 / 224 (6.70%)
    Eye disorders
    Eye irritation
         subjects affected / exposed
    6 / 236 (2.54%)
    15 / 224 (6.70%)
         occurrences all number
    7
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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