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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	2014-003186-24
Trial protocol	GB CZ DE IT NL PT
Global end of trial date	22 Jul 2020

Results information
Results version number	v1(current)
This version publication date	16 May 2021
First version publication date	16 May 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

192024-092

ISRCTN number

US NCT number

NCT02250651

WHO universal trial number (UTN)

Sponsor organisation name

Allergan Limited

Sponsor organisation address

Marlow International, The Parkway, Marlow, Buckinghamshire, United Kingdom, SL7 1YL

Public contact

EU Regulatory Dept, Allergan Limited, +44 1628 494444, ml-eu_reg_affairs@allergan.com

Scientific contact

EU Regulatory Dept, Allergan Limited, +44 1628 494444, ml-eu_reg_affairs@allergan.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

22 Jul 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Jul 2020

Was the trial ended prematurely?

Main objective of the trial

The main objective of this trial was to evaluate the efficacy and safety of bimatoprost sustained-release (SR) in patients 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?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czechia: 14

Country: Number of subjects enrolled

Germany: 9

Country: Number of subjects enrolled

Italy: 10

Country: Number of subjects enrolled

United Kingdom: 18

Country: Number of subjects enrolled

Argentina: 45

Country: Number of subjects enrolled

Canada: 23

Country: Number of subjects enrolled

Colombia: 28

Country: Number of subjects enrolled

Egypt: 7

Country: Number of subjects enrolled

Malaysia: 5

Country: Number of subjects enrolled

New Zealand: 7

Country: Number of subjects enrolled

Singapore: 8

Country: Number of subjects enrolled

South Africa: 13

Country: Number of subjects enrolled

Korea, Republic of: 11

Country: Number of subjects enrolled

Turkey: 6

Country: Number of subjects enrolled

United States: 324

Worldwide total number of subjects

528

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

285

From 65 to 84 years

237

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 528 participants (176 participants in each treatment group) were enrolled.

Period 1 title

Treatment Period 1 (Day 1 to Week 15)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Carer, Assessor, Subject

Are arms mutually exclusive

Yes

Bimatoprost SR 15 μg

Arm description

Study Eye: bimatoprost sustained-release (SR) 15 micrograms (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

Implant in pre-filled syringe

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 [without needle] procedure 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.

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

Implant in pre-filled syringe

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 [without needle] procedure 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.

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 [without needle] procedure 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	176	176	176
Received Sham or Bimatoprost SR	176	175	173
Completed	172	170	165
Not completed	4	6	11
Adverse Event	-	2	2
Protocol Deviation	1	-	-
Randomized but not Treated	-	1	3
Personal Reasons	2	3	5
Lost to follow-up	1	-	-
Reason not Specified	-	-	1

Period 2 title

Treatment Period 2 (Week 16 to Week 31)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Bimatoprost SR 15 μg

Arm description

Study Eye: bimatoprost sustained-release (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

Implant in pre-filled syringe

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 [without needle] procedure 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.

Bimatoprost SR 10 μg

Arm description

Arm type

Experimental

Investigational medicinal product name

Bimatoprost SR

Investigational medicinal product code

Other name

AGN-192024

Pharmaceutical forms

Implant in pre-filled syringe

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 [without needle] procedured 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.

Timolol 0.5%: Comparator

Arm description

Arm type

Active comparator

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 [without needle] administered 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.

Number of subjects in period 2 ^[1]	Bimatoprost SR 15 μg	Bimatoprost SR 10 μg	Timolol 0.5%: Comparator
Started	165	168	165
Completed	159	162	160
Not completed	6	6	5
Adverse Event	4	1	-
Protocol Deviation	-	1	-
Personal Reasons	2	3	2
Lost to follow-up	-	-	3
Reason not Specified	-	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: 9 participants who completed Treatment Period 1, did not receive treatment in Treatment Period 2.

Period 3 title

Treatment Period 3 (Week 32 to Week 52)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Bimatoprost SR 15 μg

Arm description

Arm type

Experimental

Investigational medicinal product name

Bimatoprost SR

Investigational medicinal product code

Other name

AGN-192024

Pharmaceutical forms

Implant in pre-filled syringe

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 [without needle] procedure 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.

Bimatoprost SR 10 μg

Arm description

Arm type

Experimental

Investigational medicinal product name

Bimatoprost SR

Investigational medicinal product code

Other name

AGN-192024

Pharmaceutical forms

Implant in pre-filled syringe

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 [without needle] procedure 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.

Timolol 0.5%: Comparator

Arm description

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 [without needle] procedure 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	147	156	159
Completed	138	152	154
Not completed	9	4	5
Adverse Event	4	1	1
Personal Reasons	2	-	2
Lost to follow-up	1	2	1
Reason not Specified	2	1	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: 19 participants who completed Treatment Period 2, did not receive treatment in Treatment Period 3.

Baseline characteristics

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Reporting group title

Bimatoprost SR 15 μg

Reporting group description

Reporting group title

Bimatoprost SR 10 μg

Reporting group description

Reporting group title

Timolol 0.5%: Comparator

Reporting group description

Reporting group values	Bimatoprost SR 15 μg	Bimatoprost SR 10 μg	Timolol 0.5%: Comparator	Total
Number of subjects	176	176	176	528
Age categorical
Units: Subjects
Adults (18-64 years)	87	94	104	285
From 65-84 years	88	80	69	237
85 years and over	1	2	3	6
Age Continuous
Units: years
arithmetic mean (standard deviation)	63.8 ( 10.7 )	62.5 ( 12.7 )	61.4 ( 12.4 )	-
Sex: Female, Male
Units: participants
Female	91	90	88	269
Male	85	86	88	259
Race/Ethnicity, Customized
Units: Subjects
White	116	115	104	335
Black or African and American	19	20	36	75
Asian	6	11	13	30
Hispanic	27	22	21	70
Other	8	8	2	18
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: millimeters of mercury (mmHg)
arithmetic mean (full range (min-max))	24.39 (18.0 to 32.0)	24.28 (15.0 to 32.0)	24.46 (17.0 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. The number of participants in the subject analysis set is the number of participants with data available for IOP at Baseline.
Units: mmHg
arithmetic mean (full range (min-max))	23.41 (18.5 to 32.0)		23.43 (15.0 to 32.0)	-

Subject analysis set title

Bimatoprost SR 10 μg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis sets values	Bimatoprost SR 10 μg
Number of subjects	175
Age categorical
Units: Subjects
Adults (18-64 years)
From 65-84 years
85 years and over
Age Continuous
Units: years
arithmetic mean (standard deviation)	( )
Sex: Female, Male
Units: participants
Female
Male
Race/Ethnicity, Customized
Units: Subjects
White
Black or African and American
Asian
Hispanic
Other
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: millimeters of mercury (mmHg)
arithmetic mean (full range (min-max))
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. The number of participants in the subject analysis set is the number of participants with data available for IOP at Baseline.
Units: mmHg
arithmetic mean (full range (min-max))	23.24 (14.0 to 32.0)

End points

Top of page

Reporting group title

Bimatoprost SR 15 μg

Reporting group description

Reporting group title

Bimatoprost SR 10 μg

Reporting group description

Reporting group title

Timolol 0.5%: Comparator

Reporting group description

Reporting group title

Bimatoprost SR 15 μg

Reporting group description

Reporting group title

Bimatoprost SR 10 μg

Reporting group description

Reporting group title

Timolol 0.5%: Comparator

Reporting group description

Reporting group title

Bimatoprost SR 15 μg

Reporting group description

Reporting group title

Bimatoprost SR 10 μg

Reporting group description

Reporting group title

Timolol 0.5%: Comparator

Reporting group description

Subject analysis set title

Bimatoprost SR 10 μg

Subject analysis set type

Sub-group analysis

Subject analysis set description

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

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End point title

Change from Baseline in Intraocular Pressure (IOP) in the Study Eye to 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. Participants from the Intent-to-treat (ITT) Population, all randomized participants, with data available for analyses.

End point type

Primary

End point timeframe

Baseline (Up to 3 days prior to Day 1 at 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	176	176	176
Units: millimeters of mercury (mmHg)
least squares mean (standard error)
Change from Baseline:Week 12,Hour 0(n=168,169,165)	-6.47 ( 0.30 )	-6.18 ( 0.30 )	-6.11 ( 0.30 )
Change from Baseline:Week 12,Hour 2(n=168,168,165)	-7.16 ( 0.28 )	-6.72 ( 0.28 )	-6.36 ( 0.29 )

Change from Baseline at Week 12, Hour 0

Statistical analysis description

The 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 mmHg 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

352

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

P-value

= 0.3738

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-1.17

upper limit

0.44

Variability estimate

Standard error of the mean

Dispersion value

0.41

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.

Change from Baseline at Week 12, Hour 0

Statistical analysis description

The 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 mmHg 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

352

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

P-value

= 0.8514

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

0.73

Variability estimate

Standard error of the mean

Dispersion value

0.41

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.

Change from Baseline at Week 12, Hour 2

Statistical analysis description

Comparison groups

Bimatoprost SR 15 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

P-value

= 0.0401

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-1.57

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.39

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.

Change from Baseline at Week 12, Hour 2

Statistical analysis description

Comparison groups

Bimatoprost SR 10 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

P-value

= 0.3621

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-1.12

upper limit

0.41

Variability estimate

Standard error of the mean

Dispersion value

0.39

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. Participants from the ITT Population, all randomized 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	170	172	172
Units: mmHg
least squares mean (standard error)	16.74 ( 0.27 )	16.92 ( 0.27 )	17.50 ( 0.27 )

Week 2, Hour 0

Statistical analysis description

Comparison groups

Bimatoprost SR 15 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

342

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

P-value

= 0.0382

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.76

Confidence interval

level

95%

sides

2-sided

lower limit

-1.48

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.36

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.

Week 2, Hour 0

Statistical analysis description

Comparison groups

Bimatoprost SR 10 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

P-value

= 0.1133

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.58

Confidence interval

level

95%

sides

2-sided

lower limit

-1.29

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.36

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)

Top of page

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. Participants from the ITT Population, all randomized 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	170	172	172
Units: mmHg
least squares mean (standard error)	16.09 ( 0.25 )	16.48 ( 0.25 )	17.19 ( 0.25 )

Week 2, Hour 2

Statistical analysis description

Comparison groups

Bimatoprost SR 15 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

342

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

P-value

= 0.0013

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.76

upper limit

-0.43

Variability estimate

Standard error of the mean

Dispersion value

0.34

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.

Week 2, Hour 2

Statistical analysis description

Comparison groups

Bimatoprost SR 10 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

P-value

= 0.0364

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.71

Confidence interval

level

95%

sides

2-sided

lower limit

-1.38

upper limit

-0.05

Variability estimate

Standard error of the mean

Dispersion value

0.34

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)

Top of page

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. Participants from the ITT Population, all randomized 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	172	171	168
Units: mmHg
least squares mean (standard error)	17.05 ( 0.28 )	16.93 ( 0.28 )	17.51 ( 0.29 )

Week 6, Hour 0

Statistical analysis description

Comparison groups

Bimatoprost SR 15 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

340

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[9]

P-value

= 0.2304

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-1.22

upper limit

0.29

Variability estimate

Standard error of the mean

Dispersion value

0.38

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.

Week 6, Hour 0

Statistical analysis description

Comparison groups

Bimatoprost SR 10 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

339

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[10]

P-value

= 0.1272

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.59

Confidence interval

level

95%

sides

2-sided

lower limit

-1.34

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.38

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)

Top of page

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. Participants from the ITT Population, all randomized 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	172	171	168
Units: mmHg
least squares mean (standard error)	16.13 ( 0.26 )	16.53 ( 0.26 )	17.18 ( 0.27 )

Week 6, Hour 2

Statistical analysis description

Comparison groups

Bimatoprost SR 15 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

340

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[11]

P-value

= 0.0038

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-1.05

Confidence interval

level

95%

sides

2-sided

lower limit

-1.76

upper limit

-0.34

Variability estimate

Standard error of the mean

Dispersion value

0.36

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.

Week 6, Hour 2

Statistical analysis description

Comparison groups

Bimatoprost SR 10 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

339

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[12]

P-value

= 0.0741

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.65

Confidence interval

level

95%

sides

2-sided

lower limit

-1.36

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.36

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)

Top of page

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. Participants from the ITT Population, all randomized 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	168	169	166
Units: mmHg
least squares mean (standard error)	17.39 ( 0.30 )	17.68 ( 0.30 )	17.75 ( 0.30 )

Week 12, Hour 0

Statistical analysis description

Comparison groups

Bimatoprost SR 15 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[13]

P-value

= 0.3738

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-1.17

upper limit

0.44

Variability estimate

Standard error of the mean

Dispersion value

0.41

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.

Week 12, Hour 0

Statistical analysis description

Comparison groups

Bimatoprost SR 10 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[14]

P-value

= 0.8514

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

0.73

Variability estimate

Standard error of the mean

Dispersion value

0.41

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)

Top of page

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. Participants from the ITT Population, all randomized 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	168	169	166
Units: mmHg
least squares mean (standard error)	16.70 ( 0.28 )	17.15 ( 0.28 )	17.50 ( 0.29 )

Week 12, Hour 2

Statistical analysis description

Comparison groups

Bimatoprost SR 15 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[15]

P-value

= 0.0401

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-1.57

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.39

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.

Week 12, Hour 2

Statistical analysis description

Comparison groups

Bimatoprost SR 10 μg v Timolol 0.5%: Comparator

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[16]

P-value

= 0.3621

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-1.12

upper limit

0.41

Variability estimate

Standard error of the mean

Dispersion value

0.39

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

Top of page

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. Participants from the ITT Population, all randomized participants, with data available for analyses.

End point type

Secondary

End point timeframe

Baseline (Up to 3 days prior to Day 1 at 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	176	176	176
Units: mmHg
least squares mean (standard error)
Change from Baseline:Week 2,Hour 0(n=170,172,171)	-7.12 ( 0.27 )	-6.94 ( 0.27 )	-6.36 ( 0.27 )
Change from Baseline:Week 2,Hour 2(n=170,171,171)	-7.77 ( 0.25 )	-7.38 ( 0.25 )	-6.67 ( 0.25 )
Change from Baseline:Week 6,Hour 0(n=172,171,167)	-6.81 ( 0.28 )	-6.93 ( 0.28 )	-6.35 ( 0.29 )
Change from Baseline:Week 6,Hour 2(n=172,170,167)	-7.74 ( 0.26 )	-7.33 ( 0.26 )	-6.69 ( 0.27 )

Change from Baseline at Week 2, Hour 0

Statistical analysis description

The 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 mmHg 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

352

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.0382

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.76

Confidence interval

level

95%

sides

2-sided

lower limit

-1.48

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.36

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.

Change from Baseline at Week 2, Hour 0

Statistical analysis description

The 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 mmHg 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

352

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.1133

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.58

Confidence interval

level

95%

sides

2-sided

lower limit

-1.29

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.36

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.

Change from Baseline at Week 2, Hour 2

Statistical analysis description

The 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 mmHg 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

352

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.0013

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.76

upper limit

-0.43

Variability estimate

Standard error of the mean

Dispersion value

0.34

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.

Change from Baseline at Week 2, Hour 2

Statistical analysis description

The 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 mmHg 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

352

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

= 0.0364

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.71

Confidence interval

level

95%

sides

2-sided

lower limit

-1.38

upper limit

-0.05

Variability estimate

Standard error of the mean

Dispersion value

0.34

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.

Change from Baseline at Week 6, Hour 0

Statistical analysis description

The 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 mmHg 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

352

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.2304

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-1.22

upper limit

0.29

Variability estimate

Standard error of the mean

Dispersion value

0.38

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.

Change from Baseline at Week 6, Hour 0

Statistical analysis description

The 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 mmHg 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

352

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

P-value

= 0.1272

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.59

Confidence interval

level

95%

sides

2-sided

lower limit

-1.34

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.38

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.

Change from Baseline at Week 6, Hour 2

Statistical analysis description

The 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 mmHg 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

352

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.0038

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-1.05

Confidence interval

level

95%

sides

2-sided

lower limit

-1.76

upper limit

-0.34

Variability estimate

Standard error of the mean

Dispersion value

0.36

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.

Change from Baseline at Week 6, Hour 2

Statistical analysis description

The 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 mmHg 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

352

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

= 0.0741

Method

MMRM

Parameter type

Least-squares Mean Difference

Point estimate

-0.65

Confidence interval

level

95%

sides

2-sided

lower limit

-1.36

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.36

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

Top of page

Timeframe for reporting adverse events

First dose of study drug to last visit (Up to approximately 20 months)

Adverse event reporting additional description

All-cause Mortality: Intent-to-treat Population included all randomized participants. Serious and Other Adverse Events: Safety Population included all participants who received at least 1 administration of study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

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

Reporting group title

Timolol 0.5%: Comparator

Reporting group description

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	36 / 176 (20.45%)	22 / 175 (12.57%)	16 / 173 (9.25%)
number of deaths (all causes)	1	0	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer
Additional description: Number of participants at risk are male participants as this adverse event is specific to males.
subjects affected / exposed ^[1]	2 / 85 (2.35%)	0 / 85 (0.00%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	2 / 176 (1.14%)	0 / 175 (0.00%)	0 / 173 (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
Breast cancer stage I
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Hepatocellular carcinoma
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Metastases to liver
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Metastases to lung
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Natural killer-cell leukaemia
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Squamous cell carcinoma of skin
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Waldenstrom’s macroglobulinaemia
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Bronchial carcinoma
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Oropharyngeal squamous cell carcinoma
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Follicular thyroid cancer
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestine carcinoma metastatic
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
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
Aortic stenosis
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Penetrating aortic ulcer
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
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
Death
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Immune system disorders
Sarcoidosis
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Reproductive system and breast disorders
Menorrhagia
Additional description: Number of participants at risk are female participants as this adverse event is specific to females.
subjects affected / exposed ^[2]	0 / 91 (0.00%)	1 / 90 (1.11%)	0 / 85 (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
Ovarian cyst
Additional description: Number of participants at risk are female participants as this adverse event is specific to females.
subjects affected / exposed ^[3]	0 / 91 (0.00%)	1 / 90 (1.11%)	0 / 85 (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
Psychiatric disorders
Bipolar disorder
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Depression
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Schizophrenia
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
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
Jaw fracture
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Procedural pain
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Fall
subjects affected / exposed	0 / 176 (0.00%)	2 / 175 (1.14%)	0 / 173 (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
Hip fracture
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Femur fracture
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Humerus fracture
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Rib fracture
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Subdural haematoma
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Product administered at inappropriate site
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 176 (0.57%)	1 / 175 (0.57%)	0 / 173 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Angina unstable
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Coronary artery disease
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Supraventricular tachycardia
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Cardiac failure congestive
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
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
Encephalopathy
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Transient ischaemic attack
subjects affected / exposed	0 / 176 (0.00%)	2 / 175 (1.14%)	0 / 173 (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
Ischaemic stroke
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Ear and labyrinth disorders
Sudden hearing loss
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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	9 / 176 (5.11%)	3 / 175 (1.71%)	0 / 173 (0.00%)
occurrences causally related to treatment / all	8 / 9	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Corneal oedema
subjects affected / exposed	2 / 176 (1.14%)	1 / 175 (0.57%)	0 / 173 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Macular oedema
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pterygium
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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 decompensation
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Visual impairment
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Retinal tear
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Gastrointestinal disorders
Ascites
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Pancreatitis
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Rectal haemorrhage
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Vomiting
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	2 / 173 (1.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis acute
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Cholelithiasis
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Renal and urinary disorders
End stage renal disease
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Acute kidney injury
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Micturition urgency
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	3 / 176 (1.70%)	0 / 175 (0.00%)	0 / 173 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Haemarthrosis
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 173 (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
Infections and infestations
Pneumonia
subjects affected / exposed	3 / 176 (1.70%)	0 / 175 (0.00%)	0 / 173 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Hypoglycaemia
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 173 (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
Hyperkalaemia
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number of participants at risk are female participants as this adverse event is specific to males.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number of participants at risk are female participants as this adverse event is specific to females.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number of participants at risk are female participants as this adverse event is specific to females.

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	133 / 176 (75.57%)	103 / 175 (58.86%)	72 / 173 (41.62%)
Investigations
Intraocular pressure increased
subjects affected / exposed	17 / 176 (9.66%)	15 / 175 (8.57%)	6 / 173 (3.47%)
occurrences all number	27	26	10
Eye disorders
Conjunctival hyperaemia
subjects affected / exposed	73 / 176 (41.48%)	48 / 175 (27.43%)	20 / 173 (11.56%)
occurrences all number	218	148	51
Corneal endothelial cell loss
subjects affected / exposed	38 / 176 (21.59%)	12 / 175 (6.86%)	2 / 173 (1.16%)
occurrences all number	39	13	3
Eye pain
subjects affected / exposed	23 / 176 (13.07%)	12 / 175 (6.86%)	9 / 173 (5.20%)
occurrences all number	40	20	12
Corneal oedema
subjects affected / exposed	21 / 176 (11.93%)	5 / 175 (2.86%)	0 / 173 (0.00%)
occurrences all number	24	5	0
Foreign body sensation in eyes
subjects affected / exposed	19 / 176 (10.80%)	18 / 175 (10.29%)	2 / 173 (1.16%)
occurrences all number	35	27	4
Dry eye
subjects affected / exposed	18 / 176 (10.23%)	12 / 175 (6.86%)	7 / 173 (4.05%)
occurrences all number	35	25	20
Conjunctival haemorrhage
subjects affected / exposed	17 / 176 (9.66%)	20 / 175 (11.43%)	15 / 173 (8.67%)
occurrences all number	24	32	24
Punctate keratitis
subjects affected / exposed	14 / 176 (7.95%)	10 / 175 (5.71%)	8 / 173 (4.62%)
occurrences all number	27	23	15
Photophobia
subjects affected / exposed	13 / 176 (7.39%)	13 / 175 (7.43%)	0 / 173 (0.00%)
occurrences all number	32	20	0
Eye irritation
subjects affected / exposed	13 / 176 (7.39%)	10 / 175 (5.71%)	9 / 173 (5.20%)
occurrences all number	27	17	15
Anterior chamber cell
subjects affected / exposed	13 / 176 (7.39%)	6 / 175 (3.43%)	1 / 173 (0.58%)
occurrences all number	14	9	1
Ocular discomfort
subjects affected / exposed	11 / 176 (6.25%)	3 / 175 (1.71%)	1 / 173 (0.58%)
occurrences all number	14	4	4
Iritis
subjects affected / exposed	9 / 176 (5.11%)	8 / 175 (4.57%)	0 / 173 (0.00%)
occurrences all number	11	12	0
Lacrimation increased
subjects affected / exposed	9 / 176 (5.11%)	7 / 175 (4.00%)	1 / 173 (0.58%)
occurrences all number	16	12	2
Vision blurred
subjects affected / exposed	7 / 176 (3.98%)	11 / 175 (6.29%)	1 / 173 (0.58%)
occurrences all number	11	16	2
Blepharitis
subjects affected / exposed	7 / 176 (3.98%)	10 / 175 (5.71%)	5 / 173 (2.89%)
occurrences all number	12	18	10
Infections and infestations
Nasopharyngitis
subjects affected / exposed	9 / 176 (5.11%)	12 / 175 (6.86%)	14 / 173 (8.09%)
occurrences all number	16	15	15

More information

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Were there any global substantial amendments to the protocol? Yes

19 Aug 2015

The following changes were implemented with Amendment 1: Modified inclusion and exclusion criteria. Updated the number of study sites. Clarified when required surgical procedures could be performed in the fellow eye. Defined a time frame and requirements for the validity of the qualifications provided by the reading center. Clarified that participants were to be followed for 12 months after their last Bimatoprost SR (or Sham) administration for safety purposes.

16 Mar 2017

The following changes were implemented with Amendment 2: Revised the screening requirement for angle eligibility confirmation in the study eye to the use of a standard clinical evaluation, modified/clarified the inclusion/exclusion criteria, clarified the statistical analyses, and changed additional procedures for participants with sickle cell disease from required to optional.

05 Jun 2018

The following changes were implemented with Amendment 3: The number of participants to enroll was reduced from 600 (200 per group) to approximately 510 (170 per group) as the observed premature discontinuation rate and IOP variability was lower than initially assumed.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Secondary: Change from Baseline in IOP in the Study Eye

Secondary: Change from Baseline in IOP in the Study Eye

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Secondary: Change from Baseline in IOP in the Study Eye

Secondary: Change from Baseline in IOP in the Study Eye

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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