Clinical trial NCT02965924
Conditions: Assess Phenylephrine on EVP and IOP
Sponsor: Mayo Clinic
Start date: 2016-10-01; Completion date: 2018-10-01
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phenylephrine hydrochloride ophthalmic solution is an alpha-1 adrenergic receptor agonist commonly used topically for dilation prior to ocular fundus examination. In the eye, phenylephrine acts locally as a potent vasoconstrictor and mydriatic by constricting ophthalmic blood vessels and the radial dilator muscle of the iris. Episcleral venous pressure (EVP) is a determinant of intraocular pressure (IOP) and can be measured non-invasively by venomanometry. Since phenylephrine is a vasoconstrictor, it may affect episcleral venous tone, but the effect on EVP is unknown. Understanding the physiology of episcleral veins helps us in better understanding of pathophysiology of glaucoma.

Detailed description:

Arms: arm 1: Subjects will receive topical phenylephrine 2.5% eye drop instilled in one eye after all baseline measurements.
Interventions: intervention 1: Phenylephrine 2.5%
Intervention descriptions: intervention 1: Instilling phenylephrine 2.5% eye drop

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Effect of Topical Phenylephrine 
2.5% on Episcleral Venous 
Pressure in Normal Human Eyes 
 
NCT# NCT02965924 
 
Date 9/9/2016 


 
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General Study Information 
 
Principal Investigator:   Arthur J. Sit, SM, MD     
 
 
 
 
 
 
 
 
Study Title:  Effect of Topical Phenylephrine 2.5% on Episcleral Venous Pressure in Normal Human Eyes   
 
Protocol version number and date:  Version 1.0, 09/09/2016    
 
 
Research Question and Aims 
 
Hypothesis: Topical phenylephrine 2.5% can change episcleral venous pressure (EVP) in normal human eyes. 
 
Aims, purpose, or objectives: Phenylephrine hydrochloride ophthalmic solution is an alpha-1 adrenergic 
receptor agonist commonly used topically for dilation prior to ocular fundus examination. In the eye, 
phenylephrine acts locally as a potent vasoconstrictor and mydriatic by constricting ophthalmic blood vessels 
and the radial dilator muscle of the iris.1,2, 3 Episcleral venous pressure (EVP) is a determinant of intraocular 
pressure (IOP) and can be measured non-invasively by venomanometry. Since phenylephrine is a 
vasoconstrictor, it may affect episcleral venous tone, but the effect on EVP is unknown. The purpose of this 
study is to assess the effect of topical phenylephrine on EVP by using a custom slit-lamp mounted 
venomanometer. 
 
Background: Phenylephrine eye drops are frequently used in ophthalmology for dilation of pupils, usually in 
combination with tropicamide 1% for routine clinical fundus examination, as well as in preoperative regimens 
for intraocular surgeries. Both concentrations of 2.5% and 10% phenylephrine have been used for this purpose. 
Maximal mydriasis occurs in 60 to 90 minutes with recovery after 5 to 7 hours. The time lag for response is 
about 15 minutes.4 In prospective randomized trials in Caucasians, phenylephrine 2.5% has been found to be as 
effective as phenylephrine 10%, with fewer systemic side-effects but in darkly pigmented irises phenylephrine 
10% appears to be more effective than phenylephrine 2.5% in pupillary dilation.2, 5, 6 Phenylephrine also is used 
as a decongestant by constricting conjunctival vessels, therefore decreasing eye redness. Gaynes7 reported of 
decrease in conjunctival venous diameter and blood velocity, and reduction of blood flow in rabbit conjunctival 
vessels. 
Several studies have been carried out to measure the effects of phenylephrine on IOP and facility of aqueous 
humor outflow in normal and glaucomatous human eyes. In several studies, phenylephrine was found to cause a 
mild reduction in IOP in both normal eyes8, 9 and eyes with open- angle glaucoma.9, 10 Other studies have 
indicated that no change or a slight increase in IOP may occur in normal eyes or eyes with open-angle glaucoma 


 
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after treatment with Phenylephrine.11-15 Tonographic studies have also been carried out with a range of results. 
Some have shown phenylephrine to increase8, 9, some to decrease13, and some to have no effect on outflow 
facility9, 13, 14, 16 in normal and glaucomatous eyes.  
Lee and Brubaker17 reported that topical phenylephrine 2.5% did not cause a clinically significant change in 
aqueous humor flow, IOP, or anterior chamber volume. Marchini18 showed that phenylephrine 10% did not 
cause any statistically significant change in IOP in patients with glaucoma and normal subjects. The effect of 
phenylephrine on the aqueous flow in normal human eyes is considered to be negligible as a result of either an 
insufficient concentration of phenylephrine in the ciliary body or the lack of influence of an α-receptor system 
on the aqueous flow.17, 19 A pharmacokinetic analysis of topical phenylephrine in the human eye revealed that 
phenylephrine is lost fairly rapidly from the anterior chamber.4 
Systemically administered phenylephrine can cause pronounced cardiovascular adverse effects, including 
increases in both systolic and diastolic blood pressure (BP) and change in heart rate (HR).20, 21 However, there is 
no conclusive evidence regarding the cardiovascular adverse effects of phenylephrine, 2.5% or 10%, eye drops 
alone or in combination with tropicamide. The largest randomized clinical trial that compared phenylephrine 
10% (n = 100) against tropicamide 1% (n = 50) did not find an increase in BP or HR up to 30 minutes after 
administration in either group.22 No change was seen with phenylephrine 2.5% at 20 to 30 minutes or at 60 
minutes or longer after topical application. Phenylephrine 2.5% is considered safe for routine use in ophthalmic 
examinations.23 
 
 
Study Design and Methods 
   
 
Visit Schedule: 
 
Description 
Visit 0 (Screening) 
Visit 1 
Time 
0.5 – 1 hour 
1.5 - 2 hours 
Purpose 
1. Informed consent  
2. Eligibility ophthalmic 
examination, medical and 
ophthalmic history. 
3. Review protocol. 
Measurements of systemic and 
ocular parameters, and response to 
topical phenylephrine  
Compensation 
0$ 
50$ 


 
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Tests 
performed:  
1. Height, weight, blood 
pressure, pulse rate 
2. Routine eye 
examination 
1. Blood pressure and pulse rate 
2. IOP measurement with 
pneumatonometer 
3. EVP measurement with 
venomanometer 
Topical phenylephrine 2.5% will be 
instilled in one eye after all baseline 
measurements. 
4. Blood pressure and pulse rate 
repeated at 15 & 60 min 
5. IOP measurement repeated at 15 
& 60 min 
6. EVP measurement repeated at 15 
& 60 min 
 
 
Medications: 
 
The subjects will be treated with the following FDA-approved topical medications: proparacaine 0.5% and 
phenylephrine 2.5%. All the eye drops will be provided from Mayo pharmacy stock supplies available in every 
ophthalmology clinic exam room. Proparacaine will be stored in a secure refrigerator that is monitored for 
medication storage. Phenylephrine will be stored in a secure area at room temperature.  
 
Clinical Methods: 
 
Visit 0 (Screening):  
 
After obtaining informed consent, we will examine each subject for general eye health to determine 
eligibility for the study, including visual acuity, slit lamp biomicroscopy, IOP measurement, gonioscopy, 
fundoscopy including optic disc and macula characterization. We will also record current medications, medical 
and surgical histories, and obtain routine physical measures (height, weight, blood pressure and pulse rate). A 
urine pregnancy test will be performed for all women who are sexually active and able to become pregnant. 
 
Visit 1: 
 
1. Intraocular Pressure: 


 
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IOP will be measured after topical anesthesia by using the pneumatonometer (Model 30 Classic, Medtronic 
Solan, Jacksonville, FL), the instrument used in research and clinical care at Mayo Clinic. There will be a 
minimum of three IOP measurements and a mean will be accepted as IOP. The difference between the three 
valid measurements should be no more than 2 mmHg. 
2. Episcleral Venous Pressure: 
EVP will be measured non-invasively using a custom-modified slit-lamp mounted venomanometer24, with 
modifications designed and constructed by the Mayo Clinic Division of Engineering.25 This device utilizes the 
pressure chamber technique, in which a clear flexible balloon is placed against the conjunctival surface of the 
eye, and the pressure is increased until an episcleral vein is noted to blanch. Our system for pressure-chamber 
based venomanometry includes a computer-controlled motor drive to increase pressure automatically, a 
transducer to record pressure, and a high-definition video camera to record vein collapse. Pressure 
measurements are synchronized with the video stream and image analysis software is used to determine the 
pressure required to collapse the vein to a specific pre-determined degree. 
3. Blood Pressure & Pulse Rate: 
All blood pressure and pulse measurements will be taken with the subject in sitting position using an 
automated blood pressure monitor. An appropriate cuff size will be used for each subject. 
Topical proparacaine will be instilled in each eye for anesthesia before IOP measurement and EVP 
measurement. After determining eligibility of subjects, baseline IOP, EVP, blood pressure and pulse rate will be 
measured in both eyes prior to instillation of phenylephrine eye drop. Each subject will then receive three 
consecutive drops of phenylephrine 2.5% instilled into the lower conjunctival sac of one eye at 1 minute 
intervals based on an Excel randomization table. The other eye won’t receive any eye drop. Subjects will be 
instructed to close their eyelids gently after instillation of each drop and to maintain closed eyes for 1 minute. 
They will be instructed to press a finger over medial canthal area against nasal bone to close nasolacrimal duct 
and reducing systemic absorption of phenylephrine. No placebo will be used for the other eye as a control. 
Blood pressure and pulse rate, IOP, and EVP will then be measured 15 minutes and 60 minutes after instillation 
of phenylephrine. For each parameter, a mean of 3 measurements will be accepted as a final value. On the day 
of the study the subjects will be asked to maintain a regular schedule with normal activities. 
Resources:   
 
Subjects will be brought to the Ophthalmology Clinic where the study will be explained and informed 
consent will be obtained. All measurements will take place in a standard examination room or the glaucoma 
clinical research area in the Ophthalmology Department and performed by the Principal Investigator or trained 
study personnel. All measurements for each subject are expected to take 120 minutes. 
 


 
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Subject Information 
 
Target accrual: 20 normal adult subjects 
 
Subject population: Participants will be recruited from local area residents, employees of Mayo Clinic, and 
prior study participants who have consented to be contacted for future research. All subjects will provide an 
ophthalmic history and receive a complete eye examination to ensure that they are eligible for the study.  
INCLUSION CRITERIA 
EXCLUSION CRITERIA 
• Either gender. 
• Adult subjects, 18 years of age and older. 
• Any self-declared ethno-racial category. 
• Medically healthy subjects.                                 
• Subjects with two healthy eyes. 
• Intraocular pressure (IOP) less than 22 mmHg 
in each eye. 
• Best-corrected visual acuity (BCVA) in each 
eye 20/50 or better. 
• Open angles in both eyes.  
• Contact lens wear stopped at least 3 days prior 
to study, and during the study.                  
• Ability to cooperate for examinations required 
for study. 
 
 
• Ophthalmic: 
• Chronic or acute ophthalmic diseases including 
glaucoma, wet type macular degeneration, uveitis 
and clinically significant cataract. 
• Evidence of ocular infection, inflammation, 
clinically significant blepharitis or conjunctivitis.   
• Cornea pathologic changes preventing reliable 
measurement. 
• Narrow anterior chamber angle. 
• Previous intraocular surgeries, laser procedures, 
and intravitreal injections. 
• Previous corneal refractive surgeries.  
• Myopia greater than -6.00 D spherical equivalent. 
• Hyperopia greater than +2.00 D spherical 
equivalent.  
• Lack of suitable episcleral vein for measurement.    
• Ocular trauma within the past 6 months. 
• Ocular infection or ocular inflammation in the 
past 3 months. 
• Ocular medication of any kind within 30 days of 
study visit. 
• Known hypersensitivity to Phenylephrine or 
topical anesthetic medication. 
• Systemic: 
• Severe hypertension: Systolic blood pressure 


 
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greater than 180 mmHg and/or diastolic blood 
pressure greater than 105 mmHg. 
• A known history of ischemic heart disease 
(angina or myocardial infarction), cerebrovascular 
accidents, cardiac arrhythmias, cerebral or aortic 
aneurysms. 
• Uncontrolled diabetes mellitus. 
• Uncontrolled hyperthyroidism. 
• Use of some systemic medications within 30 days 
prior to study including: β-adrenergic antagonists, 
α-adrenergic agonists and antagonists, calcium 
channel blockers, diuretics, vasodilators, 
monoamine oxidase inhibitors, and systemic 
steroids. 
• Participation in any interventional study within 
the past 30 days prior to study visit. 
• Women who are pregnant. 
 
Research Activity 
 
Check all that apply and complete the appropriate sections as instructed.  
  
1. 
  Drug & Device:  Drugs for which an investigational new drug application is not required. Device for 
which (i) an investigational device exemption application is not required; or the medical device is 
cleared/approved for marketing and being used in accordance with its cleared/approved labeling. (Specify in 
the Methods section) 
 
2. 
  Tests & Procedures:  Collection of data through noninvasive tests and procedures routinely employed 
in clinical practice that may include: MRI, surface EEG, echo, ultrasound, moderate exercise, muscular 
strength & flexibility testing, biometrics, cognition testing, eye exam, etc.  (Specify in the Methods section) 
 
3. 
  Data (medical record, images, or specimens):  Research involving use of existing and/or prospectively 
collected data. 
 
4. 
  Survey, Interview, Focus Group:  Research on individual or group characteristics or behavior, survey, 
interview, oral history, focus group, program evaluation, etc.  (Specify in the Methods section) 
 
 
Biospecimens – Categories 2 and 3 
 
N/A 


 
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Review of medical records, images, specimens – Category 5 
 
 
  (5b)  The study involves data that exist at the time of IRB submission and data that will be collected after 
IRB submission. Include this activity in the Methods section.  
Examples 
• The study plans to conduct a retrospective chart review and ask subjects to complete a questionnaire.  
• The study plans to include subjects previously diagnosed with a specific disease and add newly 
diagnosed subjects in the future.  
 
 
HIPAA Identifiers and Protected Health Information (PHI) 
 
Protected health information is medical data that can be linked to the subject directly or through a combination 
of indirect identifiers.  
 
Recording identifiers (including a code) during the conduct of the study allows you to return to the medical 
record or data source to delete duplicate subjects, check a missing or questionable entry, add new data points, 
etc. De-identified data is medical information that has been stripped of all HIPAA identifiers so that it cannot be 
linked back to the subject. De-identified data is rarely used in the conduct of a research study involving a chart 
review.   
 
Review the list of subject identifiers below and, if applicable, check the box next to each HIPAA identifier 
being recorded at the time of data collection or abstraction.  Identifiers apply to any subject enrolled in the 
study including Mayo Clinic staff, patients and their relatives and household members.  
 
Internal refers to the subject’s identifier that will be recorded at Mayo Clinic by the study staff. 
External refers to the subject’s identifier that will be shared outside of Mayo Clinic. 
 
Check all that apply: 
INTERNAL 
EXTERNAL 
Name 
X 
 
Mayo Clinic medical record or patient registration number, lab accession, 
specimen or radiologic image number  
X 
 
Subject ID, subject code or any other person-specific unique identifying 
number, characteristic or code that can link the subject to their medical data   
X 
 
Dates: All elements of dates [month, day, and year] directly related to an 
individual, their birth date, date of death, date of diagnosis, etc.   
Note: Recording a year only is not a unique identifier.  
X 
 
Social Security number 
 
 
Medical device identifiers and serial numbers 
 
 
Biometric identifiers, including finger and voice prints, full face photographic 
 
 


 
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images and any comparable images 
Web Universal Resource Locators (URLs), Internet Protocol (IP) address 
numbers, email address 
 
 
Street address, city, county, precinct, zip code, and their equivalent geocodes 
 
 
Phone or fax numbers 
 
 
Account, member, certificate or professional license numbers, health 
beneficiary numbers 
 
 
Vehicle identifiers and serial numbers, including license plate numbers 
 
 
Check ‘None’ when none of the identifiers listed above will be recorded, 
maintained, or shared during the conduct of this study.  (exempt category 4) 
 None 
 None 
Human Safety Aspects: 
There is a minimal risk of corneal abrasion from measurement of IOP. This is similar to the risk of corneal 
abrasion during a routine eye exam, which is a very rare event. Any subject experiencing a corneal abrasion will 
be withdrawn from further study measurements and treated.  
The risk of EVP measurement is negligible since the device only touches the conjunctiva, not the cornea.  
There is a minimal risk of eye irritation from the use of topical anesthetic eye drops. However, these drops 
are used hundreds of times daily for routine clinical care in the Ophthalmology Department with adverse 
reactions occurring very rarely. 
There is a minimal risk of systemic absorption of topical phenylephrine and raising the blood pressure. 
However we will use phenylephrine 2.5% eye drop that has been used routinely for pupil dilation and fundus 
examination in ophthalmology clinics and has been reported safe to use in clinical routine. 
 
Data Analysis 
 
 
Data Analysis Plan:  
 
All baseline measurements before instillation of phenylephrine will be compared to corresponding ones 15 
and 60 minutes after that by using two-sided t-test. There is also a comparison between treated and non-treated 
eyes for IOP and EVP measurements. Differences will be considered significant if P is less than 0.05. 
 
 
References: 
1. 
Heath P. Neo-Synephrin: Some Uses and Effects in Ophthalmology. Trans Am Ophthalmol Soc 
1936;34:231-235. 
2. 
Duffin RM, Pettit TH, Straatsma BR. 2.5% v 10% phenylephrine in maintaining mydriasis during 
cataract surgery. Arch Ophthalmol 1983;101:1903-1906. 
3. 
Haddad NJ, Moyer NJ, Riley FC, Jr. Mydriatic effect of phenylephrine hydrochloride. Am J Ophthalmol 
1970;70:729-733. 


 
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4. 
Matsumoto S, Tsuru T, Araie M, Komuro Y. Pharmacokinetics of topical phenylephrine hydrochloride 
in the normal human eye. Jpn J Ophthalmol 1982;26:338-344. 
5. 
Neuhaus RW, Hepler RS. Mydriatic effect of phenylephrine 10% (aq) vs phenylephrine 2.5% (aq). Ann 
Ophthalmol 1980;12:1159-1160. 
6. 
Tanner V, Casswell AG. A comparative study of the efficacy of 2.5% phenylephrine and 10% 
phenylephrine in pre-operative mydriasis for routine cataract surgery. Eye (Lond) 1996;10 ( Pt 1):95-98. 
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Gaynes B, Teng PY, Wanek J, Shahidi M. Feasibility of conjunctival hemodynamic measurements in 
rabbits: reproducibility, validity, and response to acute hypotension. Microcirculation 2012;19:521-529. 
8. 
Mapstone R. Normal response to pilocarpine and phenylephrine. Br J Ophthalmol 1977;61:510-511. 
9. 
Becker B, Friedenwald JS. Clinical aqueous outflow. AMA Arch Ophthalmol 1953;50:557-571. 
10. 
Posner A. Neosynephrin in glaucoma simplex. Am J Ophthalmol 1948;31:222-224. 
11. 
Kronfeld PC, McGarry HI, Smith HE. The Effect of Mydriatics Upon the Intra-ocular Pressure in So-
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12. 
Harris LS. Cycloplegic-induced intraocular pressure elevations a study of normal and open-angle 
glaucomatous eyes. Arch Ophthalmol 1968;79:242-246. 
13. 
Lee PF. The influence of epinephrine and phenylephrine on intraocular pressure. AMA Arch Ophthalmol 
1958;60:863-867. 
14. 
Schimek RA, Lieberman WJ. The influence of Cyclogyl and Neosynephrine on tonographic studies of 
miotic control in open-angle glaucoma. Am J Ophthalmol 1961;51:781-784. 
15. 
Barbee RF, Smith WO, Jr. A comparative study of mydriatic and cycloplegic agents; in human subjects 
without eye disease. Am J Ophthalmol 1957;44:617-622. 
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Becker B, Gage T, Kolker AE, Gay AJ. The effect of phenylephrine hydrochloride on the miotic-treated 
eye. Am J Ophthalmol 1959;48:313-321. 
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Lee DA, Brubaker RF. Effect of phenylephrine on aqueous humor flow. Curr Eye Res 1982;2:89-92. 
18. 
Marchini G, Babighian S, Tosi R, Perfetti S, Bonomi L. Comparative study of the effects of 2% 
ibopamine, 10% phenylephrine, and 1% tropicamide on the anterior segment. Invest Ophthalmol Vis Sci 
2003;44:281-289. 
19. 
Araie M. Acute effects of topical phenylephrine on aqueous humor dynamics and corneal endothelial 
permeability in man. Jpn J Ophthalmol 1983;27:340-345. 
20. 
Motta MM, Coblentz J, Fernandes BF, Burnier MN, Jr. Mydriatic and cardiovascular effects of 
phenylephrine 2.5% versus phenylephrine 10%, both associated with tropicamide 1%. Ophthalmic Res 
2009;42:87-89. 
21. 
Fraunfelder FW, Fraunfelder FT, Jensvold B. Adverse systemic effects from pledgets of topical ocular 
phenylephrine 10%. Am J Ophthalmol 2002;134:624-625. 
22. 
Brown MM, Brown GC, Spaeth GL. Lack of side effects from topically administered 10% 
phenylephrine eyedrops. A controlled study. Arch Ophthalmol 1980;98:487-489. 
23. 
Stavert B, McGuinness MB, Harper CA, Guymer RH, Finger RP. Cardiovascular Adverse Effects of 
Phenylephrine Eyedrops: A Systematic Review and Meta-analysis. JAMA Ophthalmol 2015;133:647-652. 
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Zeimer RC, Gieser DK, Wilensky JT, Noth JM, Mori MM, Odunukwe EE. A practical venomanometer. 
Measurement of episcleral venous pressure and assessment of the normal range. Arch Ophthalmol 
1983;101:1447-1449. 
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Sit AJ, Ekdawi NS, Malihi M, McLaren JW. A novel method for computerized measurement of 
episcleral venous pressure in humans. Experimental eye research 92:537-544.