Clinical Trial Results:
A Multi-Center, Investigator-Masked, Randomized, Crossover, Equivalence Study of the Safety and Efficacy of Once Daily Brimonidine Tartrate 0.35% Ophthalmic Suspension Compared with Brimonidine Tartrate 0.1% Ophthalmic Solution (Alphagan® P 0.1%) Dosed Three Times Daily in Subjects with Open Angle Glaucoma, Chronic Angle Closure Glaucoma with Patent Iridotomy/Iridectomy, or Ocular Hypertension

Trial information Top of page
Trial identification
Sponsor protocol code	CLR_14_12
Additional study identifiers
ISRCTN number	-
US NCT number	-
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Sun Pharma Advanced Research Company Limited
Sponsor organisation address	17/B, Mahal Industrial Estate, Off Mahakali Caves Road, near Paperbox, Andheri (E), Mumbai, India, 400093
Public contact	Hany Michail, Sun Pharma Advanced Research Company Limited, 9987096080 609664-1042, clinical.trials@sparcmail.com
Scientific contact	Hany Michail, Sun Pharma Advanced Research Company Limited, 9987096080 609664-1042, clinical.trials@sparcmail.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	08 Jun 2018
Is this the analysis of the primary completion data?	Yes
Primary completion date	08 Jun 2017
Global end of trial reached?	Yes
Global end of trial date	04 Sep 2017
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	Evaluate the safety and diurnal IOP efficacy of once daily (QD) dosing with brimonidine tartrate 0.35% ophthalmic suspension compared with brimonidine tartrate 0.1% dosed 3 times a day (TID) in subjects with chronic open-angle glaucoma, chronic angle closure glaucoma with patent iridotomy/iridectomy, pseudoexfoliation, pigment dispersion, or ocular hypertension.
Protection of trial subjects	In order to minimize potential risk to patients due to IOP elevations during the washout period, investigator could choose to substitute a parasympathomimetic or carbonic anhydrase inhibitor in place of a sympathomimetic, alpha-agonist, beta-adrenergic agent, or prostaglandin.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	29 Jul 2016
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Bulgaria: 137
Worldwide total number of subjects	137
EEA total number of subjects	137
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)	136
From 65 to 84 years	1
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	Of the enrolled 137 subjects, 135 subjects completed period 1 and 134 subjects completed period 2.
Pre-assignment
Screening details	Three subjects were screen failures. Two subjects did not meet selection criteria and one subject did not attend the randomization visit for rescreening.
Period 1
Period 1 title	Period 1
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Single blind [1]
Roles blinded	Investigator, Data analyst [2]
Blinding implementation details	This was an Investigator masked study. Randomized subjects received the study treatments from an unmasked dosing technician. Adequate measures were taken to ensure that the statistician performing the final analysis remained masked.
Arms
Are arms mutually exclusive	Yes
Arm title	Brimonidine 0.35%
Arm description	Brimonidine tartrate 0.35% ophthalmic suspension (brimonidine suspension (brimonidine 0.35%), QD
Arm type	Experimental
Investigational medicinal product name	brimonidine 0.35%
Investigational medicinal product code
Other name
Pharmaceutical forms	Eye drops, solution
Routes of administration	Ophthalmic use
Dosage and administration details	Brimonidine tartrate 0.35% ophthalmic suspension (brimonidine 0.35%), QD
Arm title	Alphagan
Arm description	alphagan 0.1%
Arm type	Active comparator
Investigational medicinal product name	brimonidine 0.35%
Investigational medicinal product code
Other name
Pharmaceutical forms	Eye drops, solution
Routes of administration	Ophthalmic use
Dosage and administration details	Brimonidine tartrate 0.35% ophthalmic suspension (brimonidine 0.35%), QD
Notes [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial. Justification: The investigator personally did not retrieve or review the study medication diary. Statistician performing final analysis was masked. An unmasked dosing technician instilled the in-office physician dispensing doses in a room separate from evaluating investigator in order to maintain investigator-masking. Subjects in brimonidine 0.35% group were taken into the dosing room at different time points, however, received study medication at the 8.00 AM time point only. [2] - The roles blinded appear inconsistent with a simple blinded trial. Justification: This was an investigator masked study. Subjects received treatment on visits from an unmasked dosing technician. The investigator personally did not review diary. designated study personnel collected and reviewed the diary at each visit to ensure treatment compliance. Statistician performing the final analysis remained masked. The randomization code for all subjects was unmasked only after all subjects completed the study and all data was recorded in the database and locked.
Number of subjects in period 1 Brimonidine 0.35% Alphagan Started 70 67 Completed 69 66 Not completed 1 1      Consent withdrawn by subject - 1      Adverse event, non-fatal 1 -
Period 2
Period 2 title	Period 2
Is this the baseline period?	No
Allocation method	Randomised - controlled
Blinding used	Double blind [3]
Roles blinded	Data analyst, Investigator
Arms
Are arms mutually exclusive	Yes
Arm title	Period 2 - Brimonidine 0.35%
Arm description	Brimonidine tartrate 0.35% ophthalmic suspension (brimonidine suspension (brimonidine 0.35%), QD
Arm type	Experimental
Investigational medicinal product name	brimonidine 0.35%
Investigational medicinal product code
Other name
Pharmaceutical forms	Eye drops, solution
Routes of administration	Ophthalmic use
Dosage and administration details	Brimonidine tartrate 0.35% ophthalmic suspension (brimonidine 0.35%), QD
Arm title	Period 2 - Alphagan
Arm description	alphagan 0.1%
Arm type	Active comparator
Investigational medicinal product name	Alphagan P® 0.1%
Investigational medicinal product code
Other name
Pharmaceutical forms	Eye drops, solution
Routes of administration	Ophthalmic use
Dosage and administration details	Brimonidine tartrate 0.1% ophthalmic solution (Alphagan P® 0.1%), TID.
Notes [3] - The roles blinded appear to be inconsistent with a double blind trial. Justification: The investigator personally did not retrieve or review the study medication diary. Statistician performing final analysis was masked. An unmasked dosing technician instilled the in-office physician dispensing doses in a room separate from evaluating investigator in order to maintain investigator-masking. Subjects in brimonidine 0.35% group were taken into the dosing room at different time points, however, received study medication at the 8.00 AM time point only.
Number of subjects in period 2 Period 2 - Brimonidine 0.35% Period 2 - Alphagan Started 69 66 Completed 68 66 Not completed 1 0      Adverse event, serious fatal 1 -

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Brimonidine 0.35%
Reporting group description	Brimonidine tartrate 0.35% ophthalmic suspension (brimonidine suspension (brimonidine 0.35%), QD
Reporting group title	Alphagan
Reporting group description	alphagan 0.1%
Reporting group values Brimonidine 0.35% Alphagan Total Number of subjects 70 67 137 Age categorical Units: Subjects     In utero 0     Preterm newborn infants (gestational age < 37 wks) 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) 0     From 65-84 years 0     85 years and over 0 Age continuous Units: years     arithmetic mean (standard deviation) 63.7 ( 10.85 ) 65.3 ( 10.17 ) - Gender categorical Units: Subjects     Female 42 47 89     Male 28 20 48

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Brimonidine 0.35%
Reporting group description	Brimonidine tartrate 0.35% ophthalmic suspension (brimonidine suspension (brimonidine 0.35%), QD
Reporting group title	Alphagan
Reporting group description	alphagan 0.1%
Reporting group title	Period 2 - Brimonidine 0.35%
Reporting group description	Brimonidine tartrate 0.35% ophthalmic suspension (brimonidine suspension (brimonidine 0.35%), QD
Reporting group title	Period 2 - Alphagan
Reporting group description	alphagan 0.1%
Subject analysis set title	Intent to treat population
Subject analysis set type	Intention-to-treat
Subject analysis set description	all subjects who were randomized into the study

End points Top of page

Primary: Intraocular pressure Top of page
End point title	Intraocular pressure
End point description
End point type	Primary
End point timeframe	Baseline to 84 days
End point values Brimonidine 0.35% Alphagan Period 2 - Brimonidine 0.35% Period 2 - Alphagan Number of subjects analysed 70 63 68 66 Units: mean     arithmetic mean (standard deviation) 15.64 ( 2.861 ) 15.73 ( 2.669 ) 15.47 ( 2.692 ) 15.85 ( 2.936 )
Statistical analysis title	Summary statistics
Statistical analysis description	Intraocular pressure measurements were summarized using continuous summary statistics by visit and time point for each eye
Comparison groups	Brimonidine 0.35% v Alphagan
Number of subjects included in analysis	133
Analysis specification	Pre-specified
Analysis type	other
P-value	= 0.9567
Method	t-test, 1-sided
Parameter type	t-test
Confidence interval
Dispersion value	0.9567

Primary: Intraocular pressure Top of page

Secondary: Mean intraocular pressure at Day 14 Top of page
End point title	Mean intraocular pressure at Day 14
End point description
End point type	Secondary
End point timeframe	Baseline to Day 14
End point values Brimonidine 0.35% Alphagan Period 2 - Brimonidine 0.35% Period 2 - Alphagan Number of subjects analysed 70 67 68 66 Units: mean     arithmetic mean (standard deviation) 15.97 ( 2.939 ) 16.49 ( 2.962 ) 15.57 ( 3.046 ) 15.80 ( 2.833 )
No statistical analyses for this end point

Secondary: Mean intraocular pressure at Day 14 Top of page

Secondary: Mean intraocular pressure at Day 28 Top of page
End point title	Mean intraocular pressure at Day 28
End point description
End point type	Secondary
End point timeframe	Baseline to day 28
End point values Brimonidine 0.35% Alphagan Period 2 - Brimonidine 0.35% Period 2 - Alphagan Number of subjects analysed 70 67 68 66 Units: mean     arithmetic mean (standard deviation) 15.70 ( 2.855 ) 15.91 ( 2.523 ) 15.17 ( 3.030 ) 15.54 ( 3.029 )
No statistical analyses for this end point

Secondary: Mean intraocular pressure at Day 28 Top of page

Secondary: Mean intraocular pressure at Day 42 Top of page
End point title	Mean intraocular pressure at Day 42
End point description
End point type	Secondary
End point timeframe	Baseline to Day 42
End point values Brimonidine 0.35% Alphagan Period 2 - Brimonidine 0.35% Period 2 - Alphagan Number of subjects analysed 70 67 68 66 Units: mean     arithmetic mean (standard deviation) 15.25 ( 2.818 ) 15.86 ( 2.522 ) 15.55 ( 3.195 ) 16.00 ( 3.064 )
No statistical analyses for this end point

Secondary: Mean intraocular pressure at Day 42 Top of page

Secondary: Mean intraocular pressure at Day 56 Top of page
End point title	Mean intraocular pressure at Day 56
End point description
End point type	Secondary
End point timeframe	Baseline to day 56
End point values Brimonidine 0.35% Alphagan Period 2 - Brimonidine 0.35% Period 2 - Alphagan Number of subjects analysed 70 67 68 66 Units: mean     arithmetic mean (standard deviation) 15.21 ( 2.467 ) 15.60 ( 2.272 ) 15.38 ( 3.128 ) 15.76 ( 3.092 )
No statistical analyses for this end point

Secondary: Mean intraocular pressure at Day 56 Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	84 days
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	19.0
Reporting groups
Reporting group title	Brimonidine 0.35%
Reporting group description	-
Reporting group title	Alphagan P
Reporting group description	-
Reporting group title	Period 2 - Brimonidine 0.35%
Reporting group description	-
Reporting group title	Period 2 - Alphagan P
Reporting group description	-
Serious adverse events Brimonidine 0.35% Alphagan P Period 2 - Brimonidine 0.35% Period 2 - Alphagan P Total subjects affected by serious adverse events      subjects affected / exposed 1 / 70 (1.43%) 0 / 67 (0.00%) 0 / 66 (0.00%) 0 / 68 (0.00%)      number of deaths (all causes) 1 0 0 0      number of deaths resulting from adverse events 1 0 0 0 Cardiac disorders Cardiac failure      subjects affected / exposed 1 / 70 (1.43%) 0 / 67 (0.00%) 0 / 66 (0.00%) 0 / 68 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Brimonidine 0.35% Alphagan P Period 2 - Brimonidine 0.35% Period 2 - Alphagan P Total subjects affected by non serious adverse events      subjects affected / exposed 36 / 70 (51.43%) 41 / 67 (61.19%) 22 / 66 (33.33%) 16 / 68 (23.53%) Nervous system disorders Somnolence      subjects affected / exposed 13 / 70 (18.57%) 5 / 67 (7.46%) 5 / 66 (7.58%) 3 / 68 (4.41%)      occurrences all number 15 5 5 3 Eye disorders ocular hyperaemia      subjects affected / exposed 23 / 70 (32.86%) 26 / 67 (38.81%) 12 / 66 (18.18%) 10 / 68 (14.71%)      occurrences all number 26 25 13 10 Gastrointestinal disorders Dry mouth      subjects affected / exposed 16 / 70 (22.86%) 17 / 67 (25.37%) 9 / 66 (13.64%) 9 / 68 (13.24%)      occurrences all number 20 20 10 11

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
16 Jul 2016	All subjects in the study were enrolled as per the Amendment 1 of the protocol dated 16 Jul 2016.
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

More information Top of page