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    Clinical Trial Results:
    Open, Observer-blind, two Parallel Group, Randomized, Multicentric Clinical Phase III Trial on the Comparison of Efficacy and Tolerability of a New Preservative-free Formulation of Brimonidine 2 mg/ml Eye Drops vs. Alphagan™ Eye Drops in Patients with Open Angle Glaucoma or Ocular Hypertension

    Summary
    EudraCT number
    		 2013-003083-31
    Trial protocol
    		 GR  
    Global end of trial date
    12 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Dec 2021
    First version publication date
    29 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Becro/OV/Brimo
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    OmniVision
    Sponsor organisation address
    Lindberghstraße 9, Puchheim, Germany, 82178
    Public contact
    CLINICAL TRIAL INFORMATION, BECRO, +30 2106729037, trials@becro.gr
    Scientific contact
    CLINICAL TRIAL INFORMATION, BECRO, +30 2106729037, trials@becro.gr
    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
    11 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the clinical trial to confirm the clinical non-inferiority of the preservative-free Brimonidine containing eye drops compared with the marketed preservative-containing Alphagan™ eye drops by the average decrease of diurnal IOP measured between the first and last visit.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 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
    Greece: 170
    Worldwide total number of subjects
    170
    EEA total number of subjects
    170
    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)
    64
    From 65 to 84 years
    103
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 170 patients who met the inclusion and exclusion criteria signed the ICF and were selected for participation. All patients switched to monotherapy with Alphagan for four weeks (screening period with induction therapy) if not already on treatment with Alphagan (no screening period required).

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    The clinical trial was performed as observer-blind because of the differences in the packaging of both drugs. The investigational medicinal product has a special container closure system. The clinical trial site has to have blind and not-blind clinical trial personnel. Blind personnel make all contacts with patients and perform all clinical trial-related examinations, whereas not-blind personnel are responsible for clinical trial medication distribution and collection.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brimonidine
    Arm description
    		 Preservative-free Brimonidine (2mg/ml) eye drops should be administered topically in the eye. The administration of the eye drops must be done as indicated: One drop in each eye twice daily, in the morning and evening approximately 12 hours apart.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Preservative-free Brimonidine (2 mg/ml) eye drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Topical use
    Dosage and administration details
    Treatment will be eye drops, which should be administered topically in the eye. The administration of the eye drops must be done as indicated: One drop in each eye twice daily, in the morning and evening approximately 12 hours apart,

    Arm title
    		 Alphagan
    Arm description
    		 Alphagan eye drops should be administered topically in the eye. The administration of the eye drops must be done as indicated: One drop in each eye twice daily, in the morning and evening approximately 12 hours apart.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Alphagan eye drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Topical use
    Dosage and administration details
    Treatment will be eye drops, which should be administered topically in the eye. The administration of the eye drops must be done as indicated: One drop in each eye twice daily, in the morning and evening approximately 12 hours apart.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The clinical trial was performed as observer-blind because of the differences in the packaging of both drugs. The investigational medicinal product has a special container closure system. The clinical trial site has to have blind and not-blind clinical trial personnel. Blind personnel make all contacts with patients and perform all clinical trial-related examinations, whereas not-blind personnel are responsible for clinical trial medication distribution and collection.
    Number of subjects in period 1
    		Brimonidine Alphagan
    Started
    86
    84
    Completed
    73
    76
    Not completed
    13
    8
         Consent withdrawn by subject
    6
    2
         High IOP
    -
    2
         Adverse event, non-fatal
    4
    2
         Lost to follow-up
    1
    2
         Prohibited concomitant treatment
    1
    -
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brimonidine
    Reporting group description
    		 Preservative-free Brimonidine (2mg/ml) eye drops should be administered topically in the eye. The administration of the eye drops must be done as indicated: One drop in each eye twice daily, in the morning and evening approximately 12 hours apart.

    Reporting group title
    Alphagan
    Reporting group description
    		 Alphagan eye drops should be administered topically in the eye. The administration of the eye drops must be done as indicated: One drop in each eye twice daily, in the morning and evening approximately 12 hours apart.

    Reporting group values
    		 Brimonidine Alphagan Total
    Number of subjects
    		 86 84 170
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 32 32 64
        From 65-84 years
    		 52 51 103
        85 years and over
    		 2 1 3
    Gender categorical
    Units: Subjects
        Female
    		 51 48 99
        Male
    		 35 36 71
    Subject analysis sets

    Subject analysis set title
    Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) population includes all those of the ITT population who had no major protocol violations, who completed IOP measurements within the allowed time frames, who completed at least 4 weeks of treatment with the last dose administered before the 4 week visit, and who did not take prohibited concurrent medication. The primary analysis is based on the PP population.

    Subject analysis set title
    Intent-to-treat (ITT) Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population includes all randomized patients who had at least one post baseline diurnal IOP-measurement.

    Subject analysis sets values
    		 Per Protocol Population Intent-to-treat (ITT) Population
    Number of subjects
    149
    170
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    56
    64
        From 65-84 years
    92
    103
        85 years and over
    1
    3
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    88
    99
        Male
    61
    71

    End points

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    End points reporting groups
    Reporting group title
    Brimonidine
    Reporting group description
    		 Preservative-free Brimonidine (2mg/ml) eye drops should be administered topically in the eye. The administration of the eye drops must be done as indicated: One drop in each eye twice daily, in the morning and evening approximately 12 hours apart.

    Reporting group title
    Alphagan
    Reporting group description
    		 Alphagan eye drops should be administered topically in the eye. The administration of the eye drops must be done as indicated: One drop in each eye twice daily, in the morning and evening approximately 12 hours apart.

    Subject analysis set title
    Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) population includes all those of the ITT population who had no major protocol violations, who completed IOP measurements within the allowed time frames, who completed at least 4 weeks of treatment with the last dose administered before the 4 week visit, and who did not take prohibited concurrent medication. The primary analysis is based on the PP population.

    Subject analysis set title
    Intent-to-treat (ITT) Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population includes all randomized patients who had at least one post baseline diurnal IOP-measurement.

    Primary: Mean diurnal IOP change from baseline to last visit

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    End point title
    		 Mean diurnal IOP change from baseline to last visit
    End point description
    The primary endpoint was the mean diurnal IOP change from baseline to last visit and the primary efficacy analysis was planned and carried out as a test of noninferiority. Then, the analysis of covariance (ANCOVA) model was used to analyse the mean change in diurnal IOP with baseline IOP as the covariate, and treatment as factor. The treatment difference and a two-sided 95% confidence interval (CI) for the difference are calculated. The preservative-free Brimonidine eye drops (Test) is considered to be non-inferior to the marketed Alphagan™ including preservative (Reference), if the upper limit of the 95% CI of the difference is < ΔΝΙ, where ΔΝΙ=1.5 mmHg is the non-inferiority criterion. The ΔΝΙ is non-inferiority margin and the value ΔΝΙ=1.5 mmHg is the commonly used tolerance criterion in non-inferiority glaucoma studies.
    End point type
    Primary
    End point timeframe
    from baseline to week 4
    End point values
    		 Brimonidine Alphagan
    Number of subjects analysed
    73
    76
    Units: mmHg
    arithmetic mean (standard deviation)
        mean IOP at baseline
    16.034 ± 2.140
    15.254 ± 2.605
        mean IOP at week 1
    15.575 ± 2.472
    15.450 ± 2.320
        mean IOP at week 2
    15.493 ± 2.301
    15.412 ± 2.221
        mean IOP at week 4
    15.370 ± 2.294
    15.489 ± 2.362
    Statistical analysis title
    		 Mean change in diurnal IOP
    Statistical analysis description
    The main efficacy parameter, diurnal IOP, was evaluated at enrolment, baseline visit, each visit (weeks 1 and 2), and at the end of the treatment period (week 4). At baseline visit and during the following visits (weeks 1, 2 and 4) the IOP was measured at 8am, 12am and 16pm. Then, the mean diurnal IOP was calculated using the measurements in both eyes. If only one eye fulfilled the criteria the mean was calculated using the measurements in the respective eye.
    Comparison groups
    Brimonidine v Alphagan
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.603
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.217
         upper limit
    		 0.012
    Variability estimate
    Standard deviation
    Notes
    [1] - The preservative-free Brimonidine 0.2%w/v eye drops (Test, T) is considered to be non-inferior to the marketed Alphagan™ 0.2%w/v eye drops containing preservative (Reference, R), if the upper limit of the 95% CI of the difference (T-R) is < ΔΝΙ, where ΔΝΙ =1.5 mmHg is the non-inferiority criterion as defined in the study protocol.

    Secondary: mean change in IOP between baseline and week 1

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    End point title
    		 mean change in IOP between baseline and week 1
    End point description
    A secondary efficacy end point was the mean change in IOP between baseline and week 1.
    End point type
    Secondary
    End point timeframe
    From baseline to week 1
    End point values
    		 Brimonidine Alphagan
    Number of subjects analysed
    73
    76
    Units: mmHg
    arithmetic mean (standard deviation)
        mean IOP at baseline
    16.034 ± 2.140
    15.254 ± 2.605
        mean IOP at week 1
    15.575 ± 2.472
    15.450 ± 2.320
    Statistical analysis title
    		 Analysis of secondary end point, baseline to wk 1
    Comparison groups
    Brimonidine v Alphagan
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.424
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.985
         upper limit
    		 0.137
    Variability estimate
    Standard deviation

    Secondary: mean change in IOP between baseline and week 2

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    End point title
    		 mean change in IOP between baseline and week 2
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to week 2
    End point values
    		 Brimonidine Alphagan
    Number of subjects analysed
    73
    76
    Units: mmHg
    arithmetic mean (standard deviation)
        mean IOP at baseline
    16.034 ± 2.140
    15.254 ± 2.605
        mean IOP at week 1
    15.575 ± 2.472
    15.450 ± 2.320
        mean IOP at week 2
    15.493 ± 2.301
    15.412 ± 2.221
    Statistical analysis title
    		 Analysis of secondary end point, baseline to wk 2
    Statistical analysis description
    A secondary efficacy end point was the mean change in IOP between baseline and week 2.
    Comparison groups
    Brimonidine v Alphagan
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.403
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.965
         upper limit
    		 0.159
    Variability estimate
    Standard deviation

    Secondary: IOP at the end of the clinical trial

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    End point title
    		 IOP at the end of the clinical trial
    End point description
    Proportion of patients with measured IOP <21 mmHg at the end of the clinical trial,
    End point type
    Secondary
    End point timeframe
    End of trial
    End point values
    		 Brimonidine Alphagan
    Number of subjects analysed
    73
    76
    Units: percent
        number (not applicable)
    100
    98.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs) that occurred during the study were documented.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Preservative-free Brimonidine 0.2%
    Reporting group description
    		 Preservative-free Brimonidine 0.2% w/v eye drops solution

    Reporting group title
    Alphagan™ 0.2%
    Reporting group description
    		 Alphagan™ 0.2% w/v eye drops solution

    Serious adverse events
    		 Preservative-free Brimonidine 0.2% Alphagan™ 0.2%
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 84 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Preservative-free Brimonidine 0.2% Alphagan™ 0.2%
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 86 (23.26%)
    16 / 84 (19.05%)
    Nervous system disorders
    Sleep disorder
         subjects affected / exposed
    3 / 86 (3.49%)
    5 / 84 (5.95%)
         occurrences all number
    3
    5
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    3 / 86 (3.49%)
    3 / 84 (3.57%)
         occurrences all number
    3
    3
    Burning
         subjects affected / exposed
    4 / 86 (4.65%)
    2 / 84 (2.38%)
         occurrences all number
    4
    2
    Stinging
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 84 (3.57%)
         occurrences all number
    0
    3
    Itching
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 84 (1.19%)
         occurrences all number
    1
    1
    Lacrimation
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Eye irritation
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 84 (2.38%)
         occurrences all number
    1
    2
    Eye dryness
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 84 (2.38%)
         occurrences all number
    2
    2
    Lower eyelid edema
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 84 (0.00%)
         occurrences all number
    2
    0
    Follicular conjunctivitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Periorbital redness
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Chemosis
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 84 (1.19%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? 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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    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.

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