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    Clinical Trial Results:
    Therapeutic Equivalence (non-inferiority), Randomized, Observer-blind, two Parallel Group, Clinical Trial for Comparing the Efficacy and Tolerability of a new Generic Formulation of 0.2% Brimonidine/0.5% Timolol fixed-Combination Eye Drops solution free of Preservatives vs. Combigan® Eye Drops solution in Patients with Open- Angle Glaucoma, or Ocular Hypertension, already on Treatment with IOP-lowering Drugs and Low Intraocular Pressure (IOP≤21 mmHg)

    Summary
    EudraCT number
    		 2015-000160-34
    Trial protocol
    		 GR  
    Global end of trial date
    17 Jun 2016

    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/BRIMTIM
    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
    05 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the clinical non-inferiority of a generic fixed combination of Brimonidine 0.2%/Timolol 0.5% eye drops solution in single dose container which is preservative-free, compared to the marketed preservative-containing Combigan® eye drops solution in patients with open angle glaucoma, or ocular hypertension, already on treatment with IOP-lowering drugs and low intraocular pressure (IOP≤21 mmHg) by examining the average change of diurnal IOP from end of study to baseline.
    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
    08 Jun 2015
    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: 180
    Worldwide total number of subjects
    180
    EEA total number of subjects
    180
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    60
    From 65 to 84 years
    117
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients who required screening period with induction therapy were administered Combigan® once daily for 4 weeks. Patients who were already on treatment with Combigan® required no screening period with induction therapy (enrolment visit coincides with baseline visit).

    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 is a preservative-free preparation, which 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 non-blind personnel are responsible for clinical trial medication distribution.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brimonidine/Timolol
    Arm description
    		 A new preservative-free formulation of Brimonidine 0.2%/Timolol 0.5% fixed combination eye drops solution in the treatment of open angle glaucoma or intraocular hypertension.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Preservative-free 0.2% Brimonidine/0.5% Timolol fixed-Combination eye drops solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution in single-dose container
    Routes of administration
    Topical use
    Dosage and administration details
    The drops solution was administered topically in the eye. The administration of the eye drops was done as indicated: One drop in each eye twice daily, once in the morning and once in the evening approximately at 21:00 (about 12 hours apart). In order to ensure that the investigator ophthalmologists remained blinded, they were not allowed to dispense the clinical trial medications to the patients nor to perform the instillations. In each centre, the dispensation and instillation of the clinical trial medications was performed by a designated member of the investigator’s staff.

    Arm title
    		 Combigan
    Arm description
    		 The preservative containing marketed medicinal product Combigan® eye drops solution in the treatment of open angle glaucoma or intraocular hypertension
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Combigan® eye drops solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Topical use
    Dosage and administration details
    The drops solution was administered topically in the eye. The administration of the eye drops was done as indicated: One drop in each eye twice daily, once in the morning and once in the evening approximately at 21:00 (about 12 hours apart). In order to ensure that the investigator ophthalmologists remained blinded, they were not allowed to dispense the clinical trial medications to the patients nor to perform the instillations. In each centre, the dispensation and instillation of the clinical trial medications was performed by a designated member of the investigator’s staff.

    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 is a preservative-free preparation, which 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 non-blind personnel are responsible for clinical trial medication distribution.
    Number of subjects in period 1
    		Brimonidine/Timolol Combigan
    Started
    91
    89
    Completed
    87
    87
    Not completed
    4
    2
         Consent withdrawn by subject
    3
    2
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brimonidine/Timolol
    Reporting group description
    		 A new preservative-free formulation of Brimonidine 0.2%/Timolol 0.5% fixed combination eye drops solution in the treatment of open angle glaucoma or intraocular hypertension.

    Reporting group title
    Combigan
    Reporting group description
    		 The preservative containing marketed medicinal product Combigan® eye drops solution in the treatment of open angle glaucoma or intraocular hypertension

    Reporting group values
    		 Brimonidine/Timolol Combigan Total
    Number of subjects
    		 91 89 180
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 33 27 60
        From 65-84 years
    		 56 61 117
        85 years and over
    		 2 1 3
    Gender categorical
    Units: Subjects
        Female
    		 60 43 103
        Male
    		 31 46 77
    Subject analysis sets

    Subject analysis set title
    Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    180 patients were randomized to treatment: 90 patients to Reference and 90 to Test. Sixteen (N=16) patients were excluded from the per protocol (PP) data set. Thus, in total 164 patients (Reference, N=82; Test, N=82) resulted in the PP data set.

    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) data set included all the randomized patients.

    Subject analysis sets values
    		 Per Protocol Population Intent-to-treat (ITT) Population
    Number of subjects
    164
    180
    Age categorical
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    90
    103
        Male
    74
    77

    End points

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    End points reporting groups
    Reporting group title
    Brimonidine/Timolol
    Reporting group description
    		 A new preservative-free formulation of Brimonidine 0.2%/Timolol 0.5% fixed combination eye drops solution in the treatment of open angle glaucoma or intraocular hypertension.

    Reporting group title
    Combigan
    Reporting group description
    		 The preservative containing marketed medicinal product Combigan® eye drops solution in the treatment of open angle glaucoma or intraocular hypertension

    Subject analysis set title
    Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    180 patients were randomized to treatment: 90 patients to Reference and 90 to Test. Sixteen (N=16) patients were excluded from the per protocol (PP) data set. Thus, in total 164 patients (Reference, N=82; Test, N=82) resulted in the PP data set.

    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) data set included all the randomized patients.

    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 of the clinical trial was the difference between the investigational products with respect to change in mean diurnal IOP in the clinical trial eye(s) between the last visit and baseline.
    End point type
    Primary
    End point timeframe
    between baseline and last visit
    End point values
    		 Brimonidine/Timolol Combigan
    Number of subjects analysed
    82
    82
    Units: mmHg
    arithmetic mean (standard deviation)
        mean IOP at baseline
    14.776 ( 2.436 )
    14.571 ( 2.219 )
        mean IOP at week 1
    14.199 ( 2.272 )
    13.949 ( 2.046 )
        mean IOP at week 2
    13.979 ( 2.175 )
    14.138 ( 1.926 )
        mean IOP at week 4
    13.979 ( 2.203 )
    13.810 ( 2.067 )
    Statistical analysis title
    		 Mean change in diurnal IOP
    Statistical analysis description
    According to the clinical trial protocol non-inferiority was tested based on the PP data set. The primary endpoint is the mean diurnal IOP decrease from baseline to last visit. 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% cnfidence interval (CI) for the difference were calculated.
    Comparison groups
    Brimonidine/Timolol v Combigan
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.066
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.488
         upper limit
    		 0.62
    Variability estimate
    Standard deviation

    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
    End point type
    Secondary
    End point timeframe
    average change of diurnal IOP measured between baseline and week 1
    End point values
    		 Brimonidine/Timolol Combigan
    Number of subjects analysed
    82
    82
    Units: mmHg
    arithmetic mean (standard deviation)
        mean IOP at baseline
    14.776 ( 2.436 )
    14.571 ( 2.219 )
        mean IOP at week 1
    14.199 ( 2.272 )
    13.949 ( 2.046 )
    Statistical analysis title
    		 Analysis of secondary end point, baseline to wk 1
    Comparison groups
    Brimonidine/Timolol v Combigan
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.121
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.368
         upper limit
    		 0.609
    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
    average change of diurnal IOP measured between baseline and week 2
    End point values
    		 Brimonidine/Timolol Combigan
    Number of subjects analysed
    82
    82
    Units: mmHg
    arithmetic mean (standard deviation)
        mean IOP at baseline
    14.776 ( 2.436 )
    14.571 ( 2.219 )
        mean IOP at week 1
    14.199 ( 2.272 )
    13.949 ( 2.046 )
        mean IOP at week 2
    13.979 ( 2.175 )
    14.138 ( 1.926 )
    Statistical analysis title
    		 Analysis of secondary end point, baseline to wk 2
    Comparison groups
    Brimonidine/Timolol v Combigan
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.269
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.773
         upper limit
    		 0.235
    Variability estimate
    Standard deviation

    Secondary: proportion of patients with measured IOP <21 mmHg at the end of study (week 4)

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    End point title
    		 proportion of patients with measured IOP <21 mmHg at the end of study (week 4)
    End point description
    proportion of patients with measured IOP <21 mmHg at the end of study (week 4)
    End point type
    Secondary
    End point timeframe
    end of study (week 4)
    End point values
    		 Brimonidine/Timolol Combigan
    Number of subjects analysed
    82
    82
    Units: percent
    number (not applicable)
        proportion of patients
    100
    100
    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
    Brimonidine 0.2%/Timolol 0.5% (Test)
    Reporting group description
    		 In this clinical trial, 180 patients were randomized to treatment: 90 patients to Combigan® (Reference) and 90 to preservative-free fixed combination Brimonidine 0.2%/Timolol 0.5% (Test). However, one patient was randomized to Reference but this patient received the Test product; thus, N=91 patients received the Test and N=89 patients received the Reference.

    Reporting group title
    Combigan®
    Reporting group description
    		 In this clinical trial, 180 patients were randomized to treatment: 90 patients to Combigan® (Reference) and 90 to preservative-free fixed combination Brimonidine 0.2%/Timolol 0.5% (Test). However, one patient was randomized to Reference but this patient received the Test product; thus, N=91 patients received the Test and N=89 patients received the Reference.

    Serious adverse events
    		 Brimonidine 0.2%/Timolol 0.5% (Test) Combigan®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 89 (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
    		 Brimonidine 0.2%/Timolol 0.5% (Test) Combigan®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 91 (8.79%)
    5 / 89 (5.62%)
    Eye disorders
    Irritation/Burining/Stinging sensation of the eye
         subjects affected / exposed
    6 / 91 (6.59%)
    4 / 89 (4.49%)
         occurrences all number
    6
    4
    Foreign body sensation
         subjects affected / exposed
    2 / 91 (2.20%)
    0 / 89 (0.00%)
         occurrences all number
    2
    0
    Dry eye
         subjects affected / exposed
    0 / 91 (0.00%)
    2 / 89 (2.25%)
         occurrences all number
    0
    2
    Ocular hyperaemia
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    Ocular lacrimation increased
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    Eye pruritus
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    Blurry vision
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 89 (1.12%)
         occurrences all number
    1
    1
    Eye irritation
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 89 (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
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