The Effect of Brimonidine on Intraocular Pressure When Dilating Routine Patients, Pressure Control and Pupil Effects
Phase: PHASE4
Conditions: Intraocular Pressure
Sponsor: Wake Forest University Health Sciences

Official Title: The Effect of Brimonidine on Intraocular Pressure When Dilating Routine 
Patients, Pressure Control and Pupil Effects 
 
NCT03959176 
 
IRB-Approved Date:  7/1/2019 
 
 

Study Title: The Effect of Brimonidine on Intraocular Pressure When Dilating Routine 
Patients, Pressure Control and Pupil Effects.  
 
Principle Investigator, Co-investigator(s): Keith Walter MD, Chaunhi Van MD, Ken 
Weinlander MD, Eva Kiehl, Richard Hesse, Eloise Joubert 
 
Sponsor or funding source: Wake Innovations 
 
Background, Rationale and Context 
 
Many biological parameters are dynamic and vary within a 24-hour cycle. Intraocular 
pressure (IOP) is one of these parameters. In addition to natural fluctuations, IOP can 
vary in relation to external factors such as exercise, medications, and eye movements [1]. 
Although patients experience daily IOP fluctuates, prolonged elevated IOP can be 
harmful. Sustained elevated IOP levels have been linked to optic nerve damage and 
diseases such as glaucoma. If IOP is not controlled, damage to the optic nerve can cause 
multiple disease states culminating in blindness. In patients with no disease, normal IOP 
ranges from 8-21 mm Hg, while glaucoma patients’ have range 20 – 50+ mm Hg. Due to 
the damage that elevated IOP can have, it is highly important for physicians to monitor 
IOP. 
 
Mydriatic eye drops that are routinely used to dilate pupils in patients presenting to 
ophthalmology clinics have also been shown to increase IOP [2]. Increased IOP has been 
seen with both parasympatholytic and sympathomimetic mydriatics [3-5].  In practice, a 
combination of tropicamide, an anticholinergic drug, and phenylephrine, an alpha-1-
adrenergic drug, is used to achieve the pupil dilation needed for routine eye exams or 
perioperative situations [6, 7]. The combination of tropicamide 1% and phenylephrine 
2.5% has been safe, effective and reliable in clinical use to adequately dilate the pupil for 
clinical examination and procedures [12]. However, these drugs have shown to increase 
IOP, and drugs such brimonidine, a selective alpha-2 agonist, have shown to reduce IOP 
[8, 9]. Brimonidine can lower IOP through a few methods. Chronic use of brimonidine 
acts through stimulating aqueous humor outflow, while using brimonidine in an acute 
setting will reduce IOP by reducing the amount of aqueous humor produce [10, 11].  
 
We propose to observe whether pre-treating patients with Brimonidine 0.2% 
(brimonidine) prior to pupil dilation and/or post-treating will be effective in controlling 
the fluctuations in IOP seen when using mydriatics. In addition to observing IOP, we will 
also observe the effects of how differing the sequence of administration of Tropicamide 
1%/Phenylephrine 2.5% combined (standard dilation drops) and brimonidine 
impacts pupil size and reactivity.  
 
Objectives 
 
Primary Objective:  To observe how differing the sequence of administration of  
Tropicamide 1%/Phenylephrine 2.5% and Brimonidine 0.2% (brimonidine 0.2%) 
influences intraocular pressure. 

• Hypothesis 1: The administration of Brimonidine 0.2% prior to 
Tropicamide 1%/Phenylephrine 2.5% will result in lower intraocular 
pressure rise than when administering Brimonidine 0.2% after initiating 
dilation with Tropicamide 1%/Phenylephrine 2.5%. 
• Hypothesis 2: The administration of both Brimonidine 0.2% and 
Tropicamide 1%/Phenylephrine 2.5% will result in lower intraocular 
pressure rise than when just administering Tropicamide 
1%/Phenylephrine 2.5% alone.  
 
Secondary Objective: To observe effect of differing the sequence of administration of 
Tropicamide 1%/Phenylephrine 2.5% and Brimonidine 0.2% on pupil size and pupil 
reactivity 
• Hypothesis 1: The administration of Brimonidine 0.2% prior to 
Tropicamide 1%/Phenylephrine 2.5% will blunt or block, or delay pupil 
dilation compared to just using Tropicamide 1%/Phenylephrine 2.5% 
alone 
• Hypothesis 2: The administration Tropicamide 1%/Phenylephrine 2.5% 
prior to Brimonidine 0.2% will lead to large pupil dilation with quicker 
reversal in pupil size than just Tropicamide 1%/Phenylephrine 2.5%. 
 
Methods and Measures  
 
• Design 
 
An interventional study looking at what order of eye drops is more effective in reducing 
intraocular pressure with pupil dilation. We will recruit 10 volunteers in each of the two groups 
(20 subjects total). In both groups, the participant’s right eye will serve as a control with only 
Tropicamide 1%/Phenylephrine 2.5% given. In the first group, the left eye will receive 
Brimonidine 0.2% prior to Tropicamide 1%/Phenylephrine 2.5%. The second group will 
receive Tropicamide 1%/Phenylephrine 2.5% prior to Brimonidine 0.2%, in their left eye. We 
will observe and record the IOP lowering benefits of the addition of brimonidine over the 
Tropicamide 1%/Phenylephrine 2.5% alone and determine if pre-treating is any better than 
post-treating. In addition, we will monitor pupil response, as we know that brimonidine may have 
some effect on the pupil dilation.  
 
We will collect the following demographic data:  age, gender, and iris color. In addition, non-
identifying color photos of the pupils may be recorded on a few representative patients in each 
group. Photos will be taken in a manner to protect patient confidentiality. Photos will be framed 
from the participants lower eyebrow, to the sides of their faces, and to the uppers nose. Photos 
will be stored on a password protected and encrypted computer or cloud-type website.  
 
• Setting 
 
The study will be performed at Wake Forest Baptist Hospital and/or Davie Medical Center. Each 
subject will be consented and have their measurements taken in a private exam room.  They will 
be returned to a waiting area in between measurements.  All concerns with measurements will be 
handled privately in the respective examination to ensure subject privacy.  
 

Subject selection criteria  
 
Subjects will be recruited through recruitment flyers and internet methods (email) (appendix 2) 
and selected to participate based on the following inclusion and exclusion criteria.  
 
• 
Inclusion criteria: Ages 18-50. Healthy with no major medical conditions. Contact lens 
wear is ok but must be not worn on the day of the study.  
• 
Females of childbearing potential must agree to use a reliable method of birth control 
while participating in this study. Reliable methods of birth control are: abstinence, oral 
contraceptives, intrauterine device (IUD), DepoProvera, tubal ligation or vasectomy of 
the partner (with confirmed negative sperm counts) in monogamous relationship (same 
partner). An acceptable, although less reliable, method involves the careful use of 
condoms and spermicidal foam or gel and/or cervical cap or sponge. A pregnancy test is 
required at least 10 days from the last normal menstrual period, if the patient is a sexually 
active female of childbearing potential. 
 
• Exclusion criteria: Diabetic, history of glaucoma, history of iris trauma, history of eye 
surgery except LASIK or PRK, pregnancy, anisocoria (unequal pupils).  
 
Sample size: 20 patients total.  
 
Study Procedure  
 
• 
Informed Consent Process: After the patient has been evaluated and meets all of the 
inclusion and exclusion criteria, Dr. Walter, or another investigator will introduce the 
study. This will occur 10 min to 24 hours before pupil dilation. The study will be 
discussed in detail and consent (appendix 1) will only be obtained once the patient has 
been given time to fully understand the study. If the patient agrees, patients will be 
dilated and intraocular pressure and pupil size will be measured at 6 time points: Baseline 
(pre drop), 15 min, after last Tropicamide 1%/Phenylephrine 2.5% drop given, 
30 min, 1 hour, 2 hours, 4 hours 
• 
Study Procedure (Approximately 4 hours): Participants will be come to the 
ophthalmology clinic where the study will be completed. Participants will be randomized 
and separated into two groups. In both groups, the participant’s right eye will serve as a 
control with only Tropicamide 1%/Phenylephrine 2.5% given. In the first group, the 
left eye will receive Brimonidine 0.2% prior to Tropicamide 1%/Phenylephrine 
2.5%. The second group will receive Tropicamide 1%/Phenylephrine 2.5% prior to 
Brimonidine 0.2.  
o IOP will be measured using the iCare tonometer device 
o Pupil size and reactivity will be measured under bright lights using a pupil gauge, 
and slit-lamp micrometer.  
• 
To prevent the dilution of the eye drops through tearing, 0.5% proparacaine 
hydrochloride (Alcaine®, Alcon Co., USA) will be delivered to each eye 5 minutes 
before administering the dilating drugs. All eye drops will be placed within the 
conjunctival sac of the lower eyelid, and patients will be directed to close their eyes 
approximately 1 minute after drop delivery to prevent loss of medication through the 
punctum in the conjunctival sac. 
  
 

Study Schematic: 1 X 4 hour participant visit  
 
Group 1 
Group 2 
Right Eye 
Left Eye 
Right Eye 
Left Eye 
 
Sham drop (none) 
 
Wait 5 minutes 
 
1 drop Tropicamide 
1%/Phenylephrine 
2.5% 
 
1 minute 
 
2nd drop 
Tropicamide 
1%/Phenylephrine 
2.5% 
 
2 drops Brimonidine 
0.2% 
 
5 minutes 
 
1 drop Tropicamide 
1%/Phenylephrine 
2.5% 
 
1 minute 
 
2nd drop 
Tropicamide 
1%/Phenylephrine 
2.5% 
 
1 drop 
Tropicamide1% 
/Phenylephrine 
2.5%  
 
Wait 1 minute 
 
2nd drop 
Tropicamide 
1%/Phenylephrine 
2.5% 
 
15 secs later 
 
Sham drop (none) 
 
1 drop Tropicamide 
1% /Phenylephrine 
2.5% 
 
Wait 1 minute 
 
2nd drop Tropicamide 
1%/Phenylephrine 
2.5% 
 
15 secs later 
 
2 drops Brimonidine 
0.2% 
 
15 min. collect Data 
set 
 
15 min. collect Data 
set 
15 min. collect Data set 
 
15 min. collect Data 
set  
 
Outcome Measures  
 
• Intraocular pressure at 6 time points: Baseline (pre-drops), 15 min after last drop 
given, then 30 min, 1 hour, 2 hours, and 4 hours 
• Pupil size at 6 time points: Baseline (pre drop), 15 min, 30 min, 1 hour, 2 hours, 4 
hours. We will measure the pupils under bright light conditions (photopic) and 
dim light conditions (scotopic). 
• Pupil’s reaction to light will be measure at 6 time points: Baseline (pre drop), 15 
min, 30 min, 1 hour, 2 hours, 4 hours. Pupil reaction will be measure either as 
none, poor, or brisk.  
 
Analytical Plan 
 
Results will be analyzed initially using descriptive statistics.  Comparison between groups 
will be done using chi square tests for proportions, and t-tests or ANOVA procedures for 
continuous variables.  Regression analysis will be performed to identify independent 
outcome predictors.  Other inferential statistical analysis will be conducted as appropriate. 
 
Human Subjects Protection  
 
Pregnancy testing will be done on all female patients, after consent and prior to 
enrollment to ensure no pregnant participates are included in the study.   
  
Subject Recruitment Methods 
 
Subjects will be recruited though placed recruitment flyers as well as electronically through an 
email with wordage directly from the flyer (appendix 2) and no students or residents will be 
recruited that are under the direct supervision of Dr. Walter. If any ophthalmology residents wish 
to volunteer (not recruited), no credit will be given for participating and their evaluations will not 
be affected. Participants will be compensated with a $30.00 Starbucks gift card. 
 
 
 

Informed Consent  
 
Signed informed consent will be obtained from each subject. The study will be introduced by 
both Dr. Walter and the study coordinator and informed consent will be obtained formally by Dr. 
Walter once the subject fully understands the study. Informed consent will be given 1-2 days or 
more prior to the subject eyes being dilated, giving them plenty of time to decide and fully 
understand the study. Final written consent will be obtained on the day the study.  
 
Confidentiality and Privacy  
 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly 
identify subjects, and maintaining all study information in a secure manner.  To help ensure 
subject privacy and confidentiality, only a unique study identifier will appear on the data 
collection form.  Any collected patient identifying information corresponding to the unique study 
identifier will be maintained on a linkage file, store separately from the data.  The linkage file 
will be kept secure, with access limited to designated study personnel.  Following data collection 
subject identifying information will be destroyed 3 years after the study is published. They will be 
destroyed by deleting all files and shredding any documents consistent with data validation and 
study design, producing an anonymous analytical data set.  Data access will be limited to study 
staff.  Data and records will be kept locked and secured, with any computer data password 
protected.  No reference to any individual participant will appear in reports, presentations, or 
publications that may arise from the study. 
 
Data and Safety Monitoring  
 
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study staff. 
 
Reporting of Unanticipated Problems, Adverse Events, or Deviations  
 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol 
changes will be promptly reported by the principal investigator or designated member of the 
research team to the IRB and sponsor or appropriate government agency if appropriate. 
 
 
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