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    Clinical Trial Results:
    Additive Effect of Twice Daily Brinzolamide 1% /Brimonidine 0.2% Fixed Dose Combination as an Adjunctive Therapy to a Prostaglandin Analogue

    Summary
    EudraCT number
    		 2015-000736-15
    Trial protocol
    		 DE   ES   GB   FR   GR  
    Global end of trial date
    27 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Dec 2018
    First version publication date
    01 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GLH694-P001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02419508
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alcon Research Ltd
    Sponsor organisation address
    6201 S. Freeway, Fort Worth, TX, United States, 76134
    Public contact
    EMEA Regulatory Affairs, Alcon Eye Care (UK) Ltd, eurmea.ra@alcon.com
    Scientific contact
    EMEA Regulatory Affairs, Alcon Eye Care (UK) Ltd, eurmea.ra@alcon.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
    27 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the additive intraocular pressure (IOP) lowering effect of brinzolamide 1%/brimonidine 0.2% (dosed twice per day (BID)) when added to a prostaglandin analogue (PGA) in subjects with open-angle glaucoma or ocular hypertension.
    Protection of trial subjects
    Prior to the start of the study, the study protocol, the informed consent and assent documents, patient instruction sheets, the Investigator’s Brochure, as well as any advertising materials used to recruit patients were submitted to institutional review boards (IRBs) and independent ethics committees (IECs). The IRB/IECs reviewed all documents and approved required documents; copies of the approval letters were provided to Alcon. Consistent with both the IRB/IEC’s requirements and all applicable regulations, the Investigators periodically provided study updates to the IRB/IEC. A patient or parent/legal guardian (if necessary, a legally authorized representative) provided informed consent, and children signed an approved assent form when appropriate. This study was conducted in accordance with Good Clinical Practices (GCP) and the ethical principles that have their origins in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Aug 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
    Spain: 28
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Greece: 14
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    Argentina: 49
    Country: Number of subjects enrolled
    Canada: 47
    Country: Number of subjects enrolled
    Chile: 2
    Worldwide total number of subjects
    188
    EEA total number of subjects
    76
    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)
    67
    From 65 to 84 years
    115
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 37 sites located in Argentina (3), Australia (4), Canada (12), Chile (3), France (1), Germany (3), Greece (2), Israel (3), Spain (3), and United Kingdom (3).

    Pre-assignment
    Screening details
    		 Of the 290 subjects enrolled in the study, 102 were exited during the Screening/Eligibility period. This reporting group includes all randomized subjects. One randomized subject did not receive investigational product and is excluded from the Full Analysis Set and the Safety Analysis Set.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SIMBRINZA + PGA
    Arm description
    		 Brinzolamide 1%/brimonidine 0.2% tartrate ophthalmic suspension, 1 drop instilled 2 times per day in affected eye(s) (09:00 and 21:00) plus designated prostaglandin analogue, 1 drop instilled in each eye once per day in the evening for 42 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brinzolamide 1%/brimonidine 0.2% tartrate ophthalmic suspension
    Investigational medicinal product code
    Other name
    SIMBRINZA® suspension
    Pharmaceutical forms
    Eye drops, suspension
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    One drop instilled 2 times per day in affected eye(s) (09:00 and 21:00) for 42 days

    Investigational medicinal product name
    Prostaglandin analogue
    Investigational medicinal product code
    Other name
    TRAVATAN® PQ, LUMIGAN®, XALATAN®
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    One drop of designated prostaglandin analogue instilled in each eye once per day in the evening for 42 days

    Arm title
    		 Vehicle + PGA
    Arm description
    		 Brinz/brim vehicle, 1 drop instilled 2 times per day in affected eye(s) (09:00 and 21:00) plus designated prostaglandin analogue, 1 drop instilled in each eye once per day in the evening for 42 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Brinz/brim vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    One drop instilled 2 times per day in affected eye(s) (09:00 and 21:00) for 42 days

    Investigational medicinal product name
    Prostaglandin analogue
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    One drop of designated prostaglandin analogue instilled in each eye once per day in the evening for 42 days

    Number of subjects in period 1
    		SIMBRINZA + PGA Vehicle + PGA
    Started
    96
    92
    Completed
    86
    88
    Not completed
    10
    4
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    9
    3
         Other - Reason not specified
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SIMBRINZA + PGA
    Reporting group description
    		 Brinzolamide 1%/brimonidine 0.2% tartrate ophthalmic suspension, 1 drop instilled 2 times per day in affected eye(s) (09:00 and 21:00) plus designated prostaglandin analogue, 1 drop instilled in each eye once per day in the evening for 42 days

    Reporting group title
    Vehicle + PGA
    Reporting group description
    		 Brinz/brim vehicle, 1 drop instilled 2 times per day in affected eye(s) (09:00 and 21:00) plus designated prostaglandin analogue, 1 drop instilled in each eye once per day in the evening for 42 days

    Reporting group values
    		 SIMBRINZA + PGA Vehicle + PGA Total
    Number of subjects
    		 96 92 188
    Age categorical
    Units: Subjects
    Age continuous
    This analysis population includes all randomized subjects.
    Units: years
        arithmetic mean (standard deviation)
    		 66.5 ( 10.65 ) 67.9 ( 11.65 ) -
    Gender categorical
    This analysis population includes all randomized subjects.
    Units: Subjects
        Female
    		 56 43 99
        Male
    		 40 49 89

    End points

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    End points reporting groups
    Reporting group title
    SIMBRINZA + PGA
    Reporting group description
    		 Brinzolamide 1%/brimonidine 0.2% tartrate ophthalmic suspension, 1 drop instilled 2 times per day in affected eye(s) (09:00 and 21:00) plus designated prostaglandin analogue, 1 drop instilled in each eye once per day in the evening for 42 days

    Reporting group title
    Vehicle + PGA
    Reporting group description
    		 Brinz/brim vehicle, 1 drop instilled 2 times per day in affected eye(s) (09:00 and 21:00) plus designated prostaglandin analogue, 1 drop instilled in each eye once per day in the evening for 42 days

    Subject analysis set title
    SIMBRINZA + PGA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in FAS with values at both baseline and time point

    Subject analysis set title
    Vehicle + PGA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in FAS with values at both baseline and time point

    Primary: Mean Change From Baseline (on PGA) in Diurnal IOP (Mean of 09:00 and 11:00 Time Points) at Week 6

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    End point title
    		 Mean Change From Baseline (on PGA) in Diurnal IOP (Mean of 09:00 and 11:00 Time Points) at Week 6
    End point description
    IOP (fluid pressure inside the eye) was measured using Goldmann applanation tonometry and averaged over the 09:00 AM and 11:00 AM time points. A more negative change from baseline indicates a greater improvement, i.e., a reduction of IOP. One eye (study eye) contributed to the analysis. This analysis population includes all randomized subjects who received a dose of study medication and had at least 1 of the 2 scheduled on-treatment visits [Full Analysis Set (FAS)]. Only subjects with a value at both baseline and time point are included in the calculation of change. Here, "N" is the number of subjects at baseline for each arm group, respectively.
    End point type
    Primary
    End point timeframe
    Baseline (BL), Week 6
    End point values
    		 SIMBRINZA + PGA Vehicle + PGA
    Number of subjects analysed
    86
    88
    Units: millimeters mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline, N=95, 92
    22.8 ( 2.39 )
    22.9 ( 2.32 )
        Mean change from baseline
    -5.6 ( 2.72 )
    -2.1 ( 2.61 )
    Statistical analysis title
    		 Mean Change From Baseline (on PGA) in Diurnal IOP
    Statistical analysis description
    Mean of 09:00 and 11:00 Time Points at Week 6
    Comparison groups
    SIMBRINZA + PGA v Vehicle + PGA
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Mean Diurnal IOP at Week 6

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    End point title
    		 Mean Diurnal IOP at Week 6
    End point description
    IOP (fluid pressure inside the eye) was measured using Goldmann applanation tonometry and averaged over the 09:00 AM and 11:00 AM time points. A higher IOP can be a greater risk factor for developing glaucoma or glaucoma progression (leading to optic nerve damage). One eye (study eye) contributed to the analysis. FAS with data available.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 SIMBRINZA + PGA Vehicle + PGA
    Number of subjects analysed
    86
    88
    Units: mmHg
        arithmetic mean (standard deviation)
    17.2 ( 3.49 )
    20.9 ( 3.59 )
    Statistical analysis title
    		 Mean Diurnal IOP at Week 6
    Comparison groups
    Vehicle + PGA v SIMBRINZA + PGA
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Mean Percentage Change From Baseline in Diurnal IOP at Week 6

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    End point title
    		 Mean Percentage Change From Baseline in Diurnal IOP at Week 6
    End point description
    IOP (fluid pressure inside the eye) was measured using Goldmann applanation tonometry and averaged over the 09:00 AM and 11:00 AM time points. A more negative percent change from baseline indicates a greater improvement, i.e., a reduction of IOP. One eye (study eye) contributed to the analysis. FAS. Only subjects with a value at both baseline and time point are included in the calculation of change. Here, "N" is the number of subjects at baseline for each arm group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6
    End point values
    		 SIMBRINZA + PGA Vehicle + PGA
    Number of subjects analysed
    86
    88
    Units: percent change
        arithmetic mean (standard deviation)
    -24.7 ( 12.17 )
    -9.5 ( 10.92 )
    Statistical analysis title
    		 Mean Percent Change From Baseline in Diurnal IOP
    Comparison groups
    SIMBRINZA + PGA v Vehicle + PGA
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Mean Change From Baseline in IOP at 11:00 at Week 6

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    End point title
    		 Mean Change From Baseline in IOP at 11:00 at Week 6
    End point description
    IOP (fluid pressure inside the eye) was measured using Goldmann applanation tonometry at 11:00 AM. A more negative change from baseline indicates a greater improvement, i.e., a reduction of IOP. One eye (study eye) contributed to the analysis. FAS. Only subjects with a value at both baseline and time point are included in the calculation of change. Here, "N" is the number of subjects at baseline for each arm group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6
    End point values
    		 SIMBRINZA + PGA Vehicle + PGA
    Number of subjects analysed
    86
    88
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline, N=95, 92
    22.4 ( 2.70 )
    22.6 ( 2.69 )
        Change from Baseline
    -7.0 ( 3.19 )
    -2.4 ( 2.78 )
    Statistical analysis title
    		 Mean Change From BL in IOP at 11:00 at Week 6
    Comparison groups
    SIMBRINZA + PGA v Vehicle + PGA
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Mean Percentage Change From Baseline in IOP at 11:00 at Week 6

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    End point title
    		 Mean Percentage Change From Baseline in IOP at 11:00 at Week 6
    End point description
    IOP (fluid pressure inside the eye) was measured using Goldmann applanation tonometry at 11:00 AM. A more negative percent change from baseline indicates a greater improvement, i.e., a reduction of IOP. One eye (study eye) contributed to the analysis. FAS. Only subjects with a value at both baseline and time point are included in the calculation of change. Here, "N" is the number of subjects at baseline for each arm group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6
    End point values
    		 SIMBRINZA + PGA Vehicle + PGA
    Number of subjects analysed
    86
    88
    Units: Percent change
        arithmetic mean (standard deviation)
    -31.3 ( 14.81 )
    -10.8 ( 11.86 )
    Statistical analysis title
    		 Mean Percent Change From BL in IOP at 11:00
    Comparison groups
    SIMBRINZA + PGA v Vehicle + PGA
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Mean Change From Baseline in IOP at 09:00 at Week 6

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    End point title
    		 Mean Change From Baseline in IOP at 09:00 at Week 6
    End point description
    IOP (fluid pressure inside the eye) was measured using Goldmann applanation tonometry at 09:00 AM. Baseline is defined as the average of the 9:00 hour values at both Eligibility visits. A more negative change from baseline indicates a greater improvement, i.e., a reduction of IOP. One eye (study eye) contributed to the analysis. FAS. Only subjects with a value at both baseline and time point are included in the calculation of change. Here, "N" is the number of subjects at baseline for each arm group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6
    End point values
    		 SIMBRINZA + PGA Vehicle + PGA
    Number of subjects analysed
    86
    88
    Units: Percent change
    arithmetic mean (standard deviation)
        Baseline, N=95, 92
    23.4 ( 2.40 )
    23.4 ( 2.22 )
        Change from baseline
    -4.9 ( 3.06 )
    -2.5 ( 2.87 )
    Statistical analysis title
    		 Mean Change From BL in IOP at 09:00 at Week 6
    Comparison groups
    SIMBRINZA + PGA v Vehicle + PGA
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Mean Percentage Change From Baseline at 09:00 at Week 6

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    End point title
    		 Mean Percentage Change From Baseline at 09:00 at Week 6
    End point description
    IOP (fluid pressure inside the eye) was measured using Goldmann applanation tonometry at 9:00 AM. Baseline is defined as the average of the 9:00 hour values at both Eligibility visits.A more negative percent change from baseline indicates a greater improvement, i.e., a reduction of IOP. One eye (study eye) contributed to the analysis. FAS. Only subjects with a value at both baseline and time point are included in the calculation of change. Here, "N" is the number of subjects at baseline for each arm group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6
    End point values
    		 SIMBRINZA + PGA Vehicle + PGA
    Number of subjects analysed
    86
    88
    Units: percent change
        arithmetic mean (standard deviation)
    -21.0 ( 13.36 )
    -10.9 ( 11.83 )
    Statistical analysis title
    		 Mean Percent Change From BL 09:00 at Week 6
    Comparison groups
    SIMBRINZA + PGA v Vehicle + PGA
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline through study completion, an average of 6 weeks.
    Adverse event reporting additional description
    Adverse Events (AEs) were obtained through solicited and spontaneous comments from subjects and through observations by the Investigator as outlined in the study protocol.This analysis population includes all subjects who received a dose of study medication (Safety Analysis Set).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    SIMBRINZA + PGA
    Reporting group description
    		 Subjects exposed to Brinz/brim + PGA

    Reporting group title
    Vehicle + PGA
    Reporting group description
    		 Subjects exposed to brinz/brim vehicle + PGA

    Serious adverse events
    		 SIMBRINZA + PGA Vehicle + PGA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (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
    		 SIMBRINZA + PGA Vehicle + PGA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 95 (10.53%)
    1 / 92 (1.09%)
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    5 / 95 (5.26%)
    1 / 92 (1.09%)
         occurrences all number
    9
    1
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    5 / 95 (5.26%)
    0 / 92 (0.00%)
         occurrences all number
    5
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2017
    Removed an IOP collection time point at all visits to reduce subject commitment and aid in recruitment. Reduced the entry IOP, allowing more subjects to be eligible while maintaining an IOP baseline that was reasonable to observe the efficacy.

    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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