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    Clinical Trial Results:
    The Efficacy and Safety of Bimatoprost SR in Patients With Open-angle Glaucoma or Ocular Hypertension

    Summary
    EudraCT number
    		 2014-003037-26
    Trial protocol
    		 HU   AT   BE   ES   DK   FR  
    Global end of trial date
    19 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jun 2020
    First version publication date
    14 Jun 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    192024-091
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02247804
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allergan
    Sponsor organisation address
    1st Floor, Marlow International, The Parkway, Marlow Buckinghamshire, United Kingdom, SL7 1YL
    Public contact
    Clinical Trials Registry Team, Allergan plc, 001 877‐277‐8566, IR-CTRegistration@allergan.com
    Scientific contact
    Therapeutic Area, Head, Allergan plc, 001 862-261-7000, IR-CTRegistration@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
    19 Jul 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to evaluate the efficacy and safety of bimatoprost SR in participants with open-angle glaucoma or ocular hypertension. The study includes a 12-month treatment period with an 8-month extended follow-up.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Dec 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 8 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Brazil: 23
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Peru: 7
    Country: Number of subjects enrolled
    Philippines: 26
    Country: Number of subjects enrolled
    Poland: 44
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 421
    Worldwide total number of subjects
    594
    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)
    310
    From 65 to 84 years
    278
    85 years and over
    6

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 594 participants (198 participants in each treatment group) were enrolled.

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bimatoprost SR 15 μg
    Arm description
    		 Study Eye: bimatoprost SR 15 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bimatoprost SR
    Investigational medicinal product code
    Other name
    AGN-192024
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Bimatoprost SR administered in the study eye on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol 0.5%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Investigational medicinal product name
    Sham: Applicator Without Needle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Sham administered on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol Vehicle (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol vehicle administered once in the morning and once in the evening for up to 20 months.

    Arm title
    		 Bimatoprost SR 10 μg
    Arm description
    		 Study Eye: bimatoprost SR 10 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bimatoprost SR
    Investigational medicinal product code
    Other name
    AGN-192024
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Bimatoprost SR administered in the study eye on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol 0.5%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Investigational medicinal product name
    Sham: Applicator Without Needle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Sham administered on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol Vehicle (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol vehicle administered once in the morning and once in the evening for up to 20 months.

    Arm title
    		 Timolol 0.5%: Comparator
    Arm description
    		 Study Eye and Non-Study Eye: sham administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Timolol 0.5%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Investigational medicinal product name
    Sham: Applicator Without Needle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Sham administered on Day 1, Week 16, and Week 32.

    Number of subjects in period 1
    		Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Started
    198
    198
    198
    Received (Sham or Bimatoprost SR)
    193
    197
    197
    Completed
    176
    194
    190
    Not completed
    22
    4
    8
         Adverse event, non-fatal
    9
    2
    -
         Protocol Deviation
    -
    -
    1
         Randomized but not Treated
    5
    1
    1
         Personal Reasons
    7
    1
    2
         Lost to follow-up
    1
    -
    2
         Lack of efficacy
    -
    -
    2
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bimatoprost SR 15 μg
    Arm description
    		 Study Eye: bimatoprost SR 15 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bimatoprost SR
    Investigational medicinal product code
    Other name
    AGN-192024
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Bimatoprost SR administered in the study eye on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol 0.5%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Investigational medicinal product name
    Sham: Applicator Without Needle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Sham administered on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol Vehicle (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol vehicle administered once in the morning and once in the evening for up to 20 months.

    Arm title
    		 Bimatoprost SR 10 μg
    Arm description
    		 Study Eye: bimatoprost SR 10 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bimatoprost SR
    Investigational medicinal product code
    Other name
    AGN-192024
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Bimatoprost SR administered in the study eye on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol 0.5%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Investigational medicinal product name
    Sham: Applicator Without Needle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Sham administered on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol Vehicle (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol vehicle administered once in the morning and once in the evening for up to 20 months.

    Arm title
    		 Timolol 0.5%: Comparator
    Arm description
    		 Study Eye and Non-Study Eye: sham administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Timolol 0.5%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Investigational medicinal product name
    Sham: Applicator Without Needle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Sham administered on Day 1, Week 16, and Week 32.

    Number of subjects in period 2 [1]
    		Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Started
    172
    191
    187
    Completed
    164
    186
    179
    Not completed
    8
    5
    8
         Adverse event, non-fatal
    6
    3
    3
         Personal Reasons
    2
    1
    1
         Lost to follow-up
    -
    1
    1
         Reason not Specified
    -
    -
    2
         Lack of efficacy
    -
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 10 participants who completed Treatment Period 1, did not receive treatment in Treatment Period 2.
    Period 3
    Period 3 title
    Treatment Period 3
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bimatoprost SR 15 μg
    Arm description
    		 Study Eye: bimatoprost SR 15 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bimatoprost SR
    Investigational medicinal product code
    Other name
    AGN-192024
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Bimatoprost SR administered in the study eye on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol 0.5%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Investigational medicinal product name
    Sham: Applicator Without Needle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Sham administered on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol Vehicle (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol vehicle administered once in the morning and once in the evening for up to 20 months.

    Arm title
    		 Bimatoprost SR 10 μg
    Arm description
    		 Study Eye: bimatoprost SR 10 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bimatoprost SR
    Investigational medicinal product code
    Other name
    AGN-192024
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Bimatoprost SR administered in the study eye on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol 0.5%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Investigational medicinal product name
    Sham: Applicator Without Needle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Sham administered on Day 1, Week 16, and Week 32.

    Investigational medicinal product name
    Timolol Vehicle (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol vehicle administered once in the morning and once in the evening for up to 20 months.

    Arm title
    		 Timolol 0.5%: Comparator
    Arm description
    		 Study Eye and Non-Study Eye: sham administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Timolol 0.5%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Investigational medicinal product name
    Sham: Applicator Without Needle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Sham administered on Day 1, Week 16, and Week 32.

    Number of subjects in period 3 [2]
    		Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Started
    158
    183
    177
    Completed
    147
    173
    167
    Not completed
    11
    10
    10
         Adverse event, non-fatal
    4
    3
    3
         Personal Reasons
    4
    3
    2
         Lost to follow-up
    1
    2
    2
         Reason not Specified
    2
    1
    3
         Lack of efficacy
    -
    1
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 11 participants who completed Treatment Period 2, did not receive treatment in Treatment Period 3.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Bimatoprost SR 15 μg
    Reporting group description
    		 Study Eye: bimatoprost SR 15 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Reporting group title
    Bimatoprost SR 10 μg
    Reporting group description
    		 Study Eye: bimatoprost SR 10 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Reporting group title
    Timolol 0.5%: Comparator
    Reporting group description
    		 Study Eye and Non-Study Eye: sham administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Reporting group values
    		 Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator Total
    Number of subjects
    		 198 198 198 594
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 100 103 107 310
        From 65-84 years
    		 95 93 90 278
        85 years and over
    		 3 2 1 6
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.5 ( 13.0 ) 62.6 ( 11.5 ) 62.5 ( 11.0 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 96 86 106 288
        Male
    		 102 112 92 306
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 122 123 130 375
        Black or African American
    		 30 31 21 82
        Asian
    		 12 17 16 45
        Hispanic
    		 27 23 25 75
        Other
    		 6 4 5 15
        Not Reported
    		 1 0 1 2
    Intraocular Pressure (IOP) at Hour 0
    IOP is a measurement of the fluid pressure inside the study eye. Measurements were taken at Hours 0 and 2. The study eye is defined as the eye that meets the entry criteria. If both eyes meet the entry criteria, the eye with the higher IOP at Baseline Hour 0 will be selected as the study eye. If both eyes had the same IOP at Hour 0, then the right eye was designated as the study eye.
    Units: mm Hg
        arithmetic mean (full range (min-max))
    		 24.76 (18.0 to 32.0) 24.64 (21.5 to 32.0) 24.63 (16.0 to 32.0) -
    Intraocular Pressure (IOP) at Hour 2
    IOP is a measurement of the fluid pressure inside the study eye. Measurements were taken at Hours 0 and 2. The study eye is defined as the eye that meets the entry criteria. If both eyes meet the entry criteria, the eye with the higher IOP at Baseline Hour 0 will be selected as the study eye. If both eyes had the same IOP at Hour 0, then the right eye was designated as the study eye.
    Units: mm Hg
        arithmetic mean (full range (min-max))
    		 23.56 (19.0 to 32.0) 23.29 (19.0 to 32.0) 23.19 (16.0 to 32.0) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Bimatoprost SR 15 μg
    Reporting group description
    		 Study Eye: bimatoprost SR 15 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Reporting group title
    Bimatoprost SR 10 μg
    Reporting group description
    		 Study Eye: bimatoprost SR 10 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Reporting group title
    Timolol 0.5%: Comparator
    Reporting group description
    		 Study Eye and Non-Study Eye: sham administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.
    Reporting group title
    Bimatoprost SR 15 μg
    Reporting group description
    		 Study Eye: bimatoprost SR 15 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Reporting group title
    Bimatoprost SR 10 μg
    Reporting group description
    		 Study Eye: bimatoprost SR 10 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Reporting group title
    Timolol 0.5%: Comparator
    Reporting group description
    		 Study Eye and Non-Study Eye: sham administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.
    Reporting group title
    Bimatoprost SR 15 μg
    Reporting group description
    		 Study Eye: bimatoprost SR 15 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Reporting group title
    Bimatoprost SR 10 μg
    Reporting group description
    		 Study Eye: bimatoprost SR 10 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Reporting group title
    Timolol 0.5%: Comparator
    Reporting group description
    		 Study Eye and Non-Study Eye: sham administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Primary: Change from Baseline in IOP in the Study Eye at Week 12 (Hours 0 and 2)

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    End point title
    		 Change from Baseline in IOP in the Study Eye at Week 12 (Hours 0 and 2)
    End point description
    IOP is a measurement of the fluid pressure inside the study eye. Measurements were taken at Hours 0 and 2. The study eye is defined as the eye that meets the entry criteria. If both eyes meet the entry criteria, the eye with the higher IOP at Baseline Hour 0 will be selected as the study eye. If both eyes had the same IOP at Hour 0, then the right eye was designated as the study eye. A mixed-effects model with repeated measures (MMRM) was used for analyses. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening. Intent-to-treat (ITT) population was defined as all randomised participants. Number analysed is the number of participants with evaluable data at the given time point.
    End point type
    Primary
    End point timeframe
    Baseline (Hours 0 and 2) to Week 12 (Hours 0 and 2)
    End point values
    		 Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Number of subjects analysed
    198
    198
    198
    Units: millimeters of mercury (mm Hg)
    least squares mean (standard error)
        Change from Baseline:Hour 0,Week 12(n=185,192,191)
    -6.46 ( 0.29 )
    -6.38 ( 0.28 )
    -6.05 ( 0.28 )
        Change from Baseline:Hour 2,Week 12(n=183,192,191)
    -7.18 ( 0.26 )
    -6.69 ( 0.25 )
    -6.48 ( 0.25 )
    Statistical analysis title
    		 Change from Baseline Week 12, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Week 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.295
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.17
         upper limit
    		 0.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Notes
    [1] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Change from Baseline Week 12, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Week 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.3904
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.09
         upper limit
    		 0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Notes
    [2] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Change from Baseline Week 12, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Week 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.0464
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 -0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [3] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Change from Baseline Week 12, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Week 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    P-value
    		 = 0.5383
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [4] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.

    Primary: IOP in the Study Eye at Week 2 (Hour 0)

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    End point title
    		 IOP in the Study Eye at Week 2 (Hour 0)
    End point description
    IOP is a measurement of the fluid pressure inside the study eye. Measurements were taken at Hours 0 and 2. The study eye is defined as the eye that meets the entry criteria. If both eyes meet the entry criteria, the eye with the higher IOP at Baseline Hour 0 will be selected as the study eye. If both eyes had the same IOP at Hour 0, then the right eye was designated as the study eye. MMRM was used for analyses. ITT population was defined as all randomised participants. Overall number of participants analysed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Week 2 (Hour 0)
    End point values
    		 Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Number of subjects analysed
    191
    196
    196
    Units: mm Hg
        least squares mean (standard error)
    16.82 ( 0.25 )
    17.02 ( 0.25 )
    17.83 ( 0.25 )
    Statistical analysis title
    		 Week 2, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 = 0.0033
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.68
         upper limit
    		 -0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Notes
    [5] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Week 2, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    P-value
    		 = 0.0187
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.47
         upper limit
    		 -0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Notes
    [6] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.

    Primary: IOP in the Study Eye at Week 2 (Hour 2)

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    End point title
    		 IOP in the Study Eye at Week 2 (Hour 2)
    End point description
    IOP is a measurement of the fluid pressure inside the study eye. Measurements were taken at Hours 0 and 2. The study eye is defined as the eye that meets the entry criteria. If both eyes meet the entry criteria, the eye with the higher IOP at Baseline Hour 0 will be selected as the study eye. If both eyes had the same IOP at Hour 0, then the right eye was designated as the study eye. MMRM was used for analyses. ITT population was defined as all randomised participants. Overall number of participants analysed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Week 2 (Hour 2)
    End point values
    		 Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Number of subjects analysed
    191
    196
    196
    Units: mm Hg
        least squares mean (standard error)
    16.48 ( 0.22 )
    16.42 ( 0.22 )
    17.33 ( 0.22 )
    Statistical analysis title
    		 Week 2, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    P-value
    		 = 0.0057
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.45
         upper limit
    		 -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31
    Notes
    [7] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Week 2, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    P-value
    		 = 0.0031
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 -0.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Notes
    [8] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.

    Primary: IOP in the Study Eye at Week 6 (Hour 0)

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    End point title
    		 IOP in the Study Eye at Week 6 (Hour 0)
    End point description
    IOP is a measurement of the fluid pressure inside the study eye. Measurements were taken at Hours 0 and 2. The study eye is defined as the eye that meets the entry criteria. If both eyes meet the entry criteria, the eye with the higher IOP at Baseline Hour 0 will be selected as the study eye. If both eyes had the same IOP at Hour 0, then the right eye was designated as the study eye. MMRM was used for analyses. ITT population was defined as all randomised participants. Overall number of participants analysed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Week 6 (Hour 0)
    End point values
    		 Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Number of subjects analysed
    188
    197
    194
    Units: mm Hg
        least squares mean (standard error)
    17.08 ( 0.24 )
    16.88 ( 0.23 )
    17.71 ( 0.24 )
    Statistical analysis title
    		 Week 6, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    P-value
    		 = 0.0547
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.26
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [9] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Week 6, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    P-value
    		 = 0.0107
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.46
         upper limit
    		 -0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [10] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.

    Primary: IOP in the Study Eye at Week 6 (Hour 2)

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    End point title
    		 IOP in the Study Eye at Week 6 (Hour 2)
    End point description
    IOP is a measurement of the fluid pressure inside the study eye. Measurements were taken at Hours 0 and 2. The study eye is defined as the eye that meets the entry criteria. If both eyes meet the entry criteria, the eye with the higher IOP at Baseline Hour 0 will be selected as the study eye. If both eyes had the same IOP at Hour 0, then the right eye was designated as the study eye. MMRM was used for analyses. ITT population was defined as all randomised participants. Overall number of participants analysed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Week 6 (Hour 2)
    End point values
    		 Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Number of subjects analysed
    187
    197
    193
    Units: mm Hg
        least squares mean (standard error)
    16.62 ( 0.23 )
    16.51 ( 0.22 )
    17.16 ( 0.23 )
    Statistical analysis title
    		 Week 6, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    P-value
    		 = 0.086
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.16
         upper limit
    		 0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [11] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Week 6, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    P-value
    		 = 0.0362
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.27
         upper limit
    		 -0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31
    Notes
    [12] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.

    Primary: IOP in the Study Eye at Week 12 (Hour 0)

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    End point title
    		 IOP in the Study Eye at Week 12 (Hour 0)
    End point description
    IOP is a measurement of the fluid pressure inside the study eye. Measurements were taken at Hours 0 and 2. The study eye is defined as the eye that meets the entry criteria. If both eyes meet the entry criteria, the eye with the higher IOP at Baseline Hour 0 will be selected as the study eye. If both eyes had the same IOP at Hour 0, then the right eye was designated as the study eye. MMRM was used for analyses. ITT population was defined as all randomised participants. Overall number of participants analysed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Week 12 (Hour 0)
    End point values
    		 Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Number of subjects analysed
    185
    192
    191
    Units: mm Hg
        least squares mean (standard error)
    17.53 ( 0.29 )
    17.61 ( 0.28 )
    17.94 ( 0.28 )
    Statistical analysis title
    		 Week 12, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    P-value
    		 = 0.295
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.17
         upper limit
    		 0.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Notes
    [13] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Week 12, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [14]
    P-value
    		 = 0.3904
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.09
         upper limit
    		 0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Notes
    [14] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.

    Primary: IOP in the Study Eye at Week 12 (Hour 2)

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    End point title
    		 IOP in the Study Eye at Week 12 (Hour 2)
    End point description
    IOP is a measurement of the fluid pressure inside the study eye. Measurements were taken at Hours 0 and 2. The study eye is defined as the eye that meets the entry criteria. If both eyes meet the entry criteria, the eye with the higher IOP at Baseline Hour 0 will be selected as the study eye. If both eyes had the same IOP at Hour 0, then the right eye was designated as the study eye. MMRM was used for analyses. ITT population was defined as all randomised participants. Overall number of participants analysed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Week 12 (Hour 2)
    End point values
    		 Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Number of subjects analysed
    183
    192
    191
    Units: mm Hg
        least squares mean (standard error)
    16.81 ( 0.26 )
    17.30 ( 0.25 )
    17.51 ( 0.25 )
    Statistical analysis title
    		 Week 12, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [15]
    P-value
    		 = 0.0464
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 -0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [15] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Week 12, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared non-inferior to timolol 0.5% if the upper limit of the 95% CI was ≤ 1.5 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [16]
    P-value
    		 = 0.5383
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [16] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.

    Secondary: Change from Baseline in IOP in the Study Eye

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    End point title
    		 Change from Baseline in IOP in the Study Eye
    End point description
    IOP is a measurement of the fluid pressure inside the study eye. Measurements were taken at Hours 0 and 2. The study eye is defined as the eye that meets the entry criteria. If both eyes meet the entry criteria, the eye with the higher IOP at Baseline Hour 0 will be selected as the study eye. If both eyes had the same IOP at Hour 0, then the right eye was designated as the study eye. MMRM was used for analyses. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening. ITT population was defined as all randomized participants. Number analysed is the number of participants with evaluable data at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Hours 0 and 2) to Weeks 2 and 6 (Hours 0 and 2)
    End point values
    		 Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Number of subjects analysed
    198
    198
    198
    Units: mm Hg
    least squares mean (standard error)
        Change from Baseline:Hour 0,Week 2(n=191,196,196)
    -7.17 ( 0.25 )
    -6.97 ( 0.25 )
    -6.17 ( 0.25 )
        Change from Baseline:Hour 2,Week 2(n=191,196,196)
    -7.52 ( 0.22 )
    -7.57 ( 0.22 )
    -6.67 ( 0.22 )
        Change from Baseline:Hour 0,Week 6(n=188,197,194)
    -6.91 ( 0.24 )
    -7.11 ( 0.23 )
    -6.29 ( 0.24 )
        Change from Baseline:Hour 2,Week 6(n=187,197,193)
    -7.37 ( 0.23 )
    -7.48 ( 0.22 )
    -6.83 ( 0.23 )
    Statistical analysis title
    		 Change from Baseline Week 2, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared superior to timolol 0.5% if the upper limit of the 95% CI was < 0 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.0033
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.68
         upper limit
    		 -0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Notes
    [17] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Change from Baseline Week 2, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared superior to timolol 0.5% if the upper limit of the 95% CI was < 0 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.0187
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.47
         upper limit
    		 -0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Notes
    [18] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Change from Baseline Week 2, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared superior to timolol 0.5% if the upper limit of the 95% CI was < 0 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.0057
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.45
         upper limit
    		 -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31
    Notes
    [19] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Change from Baseline Week 2, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared superior to timolol 0.5% if the upper limit of the 95% CI was < 0 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.0031
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 -0.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Notes
    [20] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Change from Baseline Week 6, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared superior to timolol 0.5% if the upper limit of the 95% CI was < 0 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.0547
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.26
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [21] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Change from Baseline Week 6, Hour 0
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared superior to timolol 0.5% if the upper limit of the 95% CI was < 0 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.0107
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.46
         upper limit
    		 -0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [22] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Change from Baseline Week 6, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 15 μg was to be declared superior to timolol 0.5% if the upper limit of the 95% CI was < 0 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 15 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.086
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.16
         upper limit
    		 0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [23] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.
    Statistical analysis title
    		 Change from Baseline Week 6, Hour 2
    Statistical analysis description
    The null hypothesis was that bimatoprost SR 10 μg was to be declared superior to timolol 0.5% if the upper limit of the 95% CI was < 0 mm Hg for all scheduled timepoints (Hours 0 and 2 at Weeks 2, 6, 12).
    Comparison groups
    Bimatoprost SR 10 μg v Timolol 0.5%: Comparator
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.0362
    Method
    		 MMRM
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.27
         upper limit
    		 -0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31
    Notes
    [24] - MMRM analyses was used with response variable:IOP time-matched change from baseline;Fixed factors: Treatment,timepoint,treatment-by-timepoint interaction and baseline IOP stratification;Covariate:Time-matched baseline IOP and timepoint by time-matched baseline IOP interaction. Unstructured covariance matrix was used.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug to last visit (Up to approximately 20 months)
    Adverse event reporting additional description
    Safety population included all participants who received at least 1 dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Bimatoprost SR 15 μg
    Reporting group description
    		 Study Eye: bimatoprost SR 15 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Reporting group title
    Bimatoprost SR 10 μg
    Reporting group description
    		 Study Eye: bimatoprost SR 10 μg administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol vehicle administered once in the morning and once in the evening for up to 20 months. Non-Study Eye: sham administration on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Reporting group title
    Timolol 0.5%: Comparator
    Reporting group description
    		 Study Eye and Non-Study Eye: sham administered on Day 1 (Period 1), Week 16 (Period 2), and Week 32 (Period 3); timolol 0.5% administered once in the morning and once in the evening for up to 20 months.

    Serious adverse events
    		 Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 193 (16.06%)
    25 / 197 (12.69%)
    18 / 197 (9.14%)
         number of deaths (all causes)
    2
    1
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 197 (1.02%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Internal haemorrhage
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 197 (0.51%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 197 (0.51%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Head injury
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 193 (1.04%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIth nerve paralysis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Corneal endothelial cell loss
         subjects affected / exposed
    12 / 193 (6.22%)
    4 / 197 (2.03%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    12 / 12
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Corneal oedema
         subjects affected / exposed
    3 / 193 (1.55%)
    2 / 197 (1.02%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Corneal touch
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular oedema
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haemorrhoids
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint instability
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 197 (0.00%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 193 (0.00%)
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bimatoprost SR 15 μg Bimatoprost SR 10 μg Timolol 0.5%: Comparator
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    143 / 193 (74.09%)
    138 / 197 (70.05%)
    105 / 197 (53.30%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    13 / 193 (6.74%)
    20 / 197 (10.15%)
    7 / 197 (3.55%)
         occurrences all number
    17
    28
    13
    Vascular disorders
    Hypertension
         subjects affected / exposed
    17 / 193 (8.81%)
    12 / 197 (6.09%)
    8 / 197 (4.06%)
         occurrences all number
    17
    16
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 193 (4.15%)
    14 / 197 (7.11%)
    7 / 197 (3.55%)
         occurrences all number
    10
    16
    7
    Visual field defect
         subjects affected / exposed
    4 / 193 (2.07%)
    10 / 197 (5.08%)
    5 / 197 (2.54%)
         occurrences all number
    5
    13
    9
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    74 / 193 (38.34%)
    60 / 197 (30.46%)
    47 / 197 (23.86%)
         occurrences all number
    193
    180
    139
    Foreign body sensation in eyes
         subjects affected / exposed
    31 / 193 (16.06%)
    23 / 197 (11.68%)
    12 / 197 (6.09%)
         occurrences all number
    58
    48
    25
    Eye pain
         subjects affected / exposed
    28 / 193 (14.51%)
    26 / 197 (13.20%)
    12 / 197 (6.09%)
         occurrences all number
    42
    43
    28
    Eye irritation
         subjects affected / exposed
    28 / 193 (14.51%)
    18 / 197 (9.14%)
    22 / 197 (11.17%)
         occurrences all number
    66
    45
    62
    Photophobia
         subjects affected / exposed
    23 / 193 (11.92%)
    19 / 197 (9.64%)
    4 / 197 (2.03%)
         occurrences all number
    40
    36
    8
    Corneal endothelial cell loss
         subjects affected / exposed
    20 / 193 (10.36%)
    14 / 197 (7.11%)
    0 / 197 (0.00%)
         occurrences all number
    20
    14
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    19 / 193 (9.84%)
    17 / 197 (8.63%)
    16 / 197 (8.12%)
         occurrences all number
    23
    23
    19
    Iritis
         subjects affected / exposed
    19 / 193 (9.84%)
    11 / 197 (5.58%)
    1 / 197 (0.51%)
         occurrences all number
    27
    13
    1
    Dry eye
         subjects affected / exposed
    17 / 193 (8.81%)
    19 / 197 (9.64%)
    12 / 197 (6.09%)
         occurrences all number
    32
    35
    24
    Punctate keratitis
         subjects affected / exposed
    16 / 193 (8.29%)
    12 / 197 (6.09%)
    14 / 197 (7.11%)
         occurrences all number
    30
    36
    40
    Lacrimation increased
         subjects affected / exposed
    13 / 193 (6.74%)
    10 / 197 (5.08%)
    12 / 197 (6.09%)
         occurrences all number
    22
    15
    22
    Vision blurred
         subjects affected / exposed
    12 / 193 (6.22%)
    10 / 197 (5.08%)
    11 / 197 (5.58%)
         occurrences all number
    20
    21
    21
    Corneal oedema
         subjects affected / exposed
    12 / 193 (6.22%)
    5 / 197 (2.54%)
    2 / 197 (1.02%)
         occurrences all number
    14
    5
    3
    Anterior chamber cell
         subjects affected / exposed
    11 / 193 (5.70%)
    9 / 197 (4.57%)
    0 / 197 (0.00%)
         occurrences all number
    16
    11
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 193 (6.74%)
    10 / 197 (5.08%)
    14 / 197 (7.11%)
         occurrences all number
    15
    10
    17
    Influenza
         subjects affected / exposed
    8 / 193 (4.15%)
    13 / 197 (6.60%)
    4 / 197 (2.03%)
         occurrences all number
    8
    15
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2015
    The following changes were implemented with Amendment 1: Protocol was amended to clarify some sections and to modify the inclusion/exclusion criteria.
    16 Mar 2017
    The following changes were implemented with Amendment 2: Protocol was amended to change the screening requirement for angle eligibility confirmation in the study eye, modify/clarify the inclusion/exclusion criteria, clarify the statistical analyses, and change additional procedures for participants with sickle cell disease from required to optional.

    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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