Clinical trial NCT03760185
Conditions: Intraoperative Floppy Iris Syndrome
Sponsor: Denver Health and Hospital Authority
Start date: 2019-01-04; Completion date: 2020-09-25
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
A novel intervention for targeting the treatment of Intraoperative Floppy Iris Syndrome.

Detailed description:
This study explores the effects that medication can have on increasing pupil dilation. Pupil dilation size is important for operative eye procedures. Decreased pupil size is related to increased complication risks in eye surgery. By exploring novel pupil dilation techniques, there is a potential to counteract the effects of poor pupil dilation that is caused by medications such as alpha-blockers. Intraoperative floppy iris syndrome is a syndrome characterized by a floppy iris (IFIS) and poor pupil dilation during surgery that is caused by BPH medications. This study evaluates treatment methods targeting IFIS.

Arms: arm 1: One eye was treated with Brimonidine Tartrate 0.2% after a 20-day washout period. Patients will treat right eye 3 times per day for 7 days of treatment. arm 2: The left eye will serve as the control for the study and will not receive the Brimonidine Tartrate 0.2% treatment
Interventions: intervention 1: Brimonidine Tartrate
Intervention descriptions: intervention 1: All subjects will apply brimonidine tartrate to one eye (right eye) only for the duration of study participation.

Protocol documents:
Prot_SAP_002.pdf: 
 
Protocol Template 
Page 1 
CF-146, Effective 7/10/11 
 
w 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Protocol #: 18- 1713 
Project Title: 
Enhanced Pupil Dilation in Patients Taking Alpha-
Blockers for Potential Treatment of Intraoperative Floppy Iris 
Syndrome using Brimonidine Tartrate 
 
 
Principal Investigator:  
Cristos Ifantides, MD 
Version Date: 
 02/22/2019  
 
 
 
 
  
 
I. Hypotheses and Specific Aims:  
 
Hypothesis:  In patients who have poor pupillary dilation secondary to 
α-1 blocker use (ex: tamsulosin), treatment with an α-2 agonist, 
such as brimonidine tartrate .2%, 7 days prior to standard 
pharmacological dilation will lead to improved pupillary dilation.   
 
Primary Aim:  To determine the average increased pupillary dilation in 
the α-2 agonist treated eye compared to the untreated eye in 
patients with a history of taking tamsulosin (or another systemic α 
blocker).   
 
Secondary Aim:  To determine the increased pupil dilation of the 
treated eye after bromidine tartrate .2% for 7 days compared to the 
initial dilation prior to brimonidine treatment.  
 
II. Background and Significance:  
 
Each year, millions of people suffer from poor pupillary dilation during 
eye exams and eye surgery. Poor pupil dilation leads to inadequate 
visualization of pathology by an eye care specialist during clinic-based 
exams. Even more importantly, the surgical work area of the eye is 
severely diminished in these patients. Narrowing a surgeon’s work area 
has significant implications for surgical safety and patient outcomes 
and contributes to higher rates of complications.1,2,3 Capsular rupture is 
one of the many complications that can occur and is estimated to cost 
the U.S. up to $35 million annually.4 
 
One cause of poor pupil dilation is due to secondary systemic 
effects of α blockers.  Poor pupil dilation in these patients has 
been newly termed Intraoperative Floppy Iris Syndrome (IFIS) .  This 
class of drugs is often prescribed in middle-aged to older men 
diagnosed with Benign Prostate Hyperplasia (BPH).  IFIS is composed 


 
Protocol Template 
Page 2 
CF-146, Effective 7/10/11 
 
of a triad of intraoperative characteristics: 1) a floppy iris that “billows” 
in response to irrigation and aspiration, 2) tendency of the iris to 
prolapse out of the wound, and 3) progressive pupil constriction during 
surgery despite standard pharmacological dilation measures.  IFIS was 
first identified as problematic in patients taking tamsulosin in 20051.   
Previous studies have indicated that the incidence of Intraoperative 
Floppy Iris Syndrome is 2% of all total patients undergoing eye 
operations (3.6 million cataract surgeries are performed in the United 
States each year)5.   In patients taking tamsulosin the incidence of IFIS 
is up to 90%6.  Simply discontinuing the α-blocker does not resolve the 
symptoms, which means any patient who has taken a tamsulosin at 
any point in their life is at high risk for having IFIS and suffering surgical 
complications. Complications include capsular rupture, loss of vitreous, 
iris prolapse, iris stroma atrophy, capsulorhexis tear, or anterior 
chamber hemorrhage.  History of tamsulosin use in operative patients 
has an associated 2.3-fold increase risk of complications compared to 
patients who have never taken tamsulosin7.  
 
For surgical ophthalmologists, poor pupil dilation is problematic 
because the smaller pupil results in less light entering the dilated eye 
and an obstructed view during surgery.  This is highlighted by the 
following diagram and equation for the area of a circle: 
 
 
 
From the above equation, we can see that an eye surgeon’s work area 
(A) inside of a circular pupil is most influenced by the radius (r). As 
dilating eye drops are applied to the eye, the radius of the pupil 
increases and the surgical work area increases exponentially. If the 
radius of a pupil doubles, the surgical work area quadruples. Similarly, 
if the dilated pupil size decreases by one half from 8mm to 4mm, the 
surgical work area decreases by a factor of four. 
 
 
III. Preliminary Studies/Progress Report:   
 
 There is currently no FDA approved cure or treatment to prevent or 
lessen the symptoms associated with IFIS.  Current research is 
targeted at identifying patients most at risk for surgical complications by 
determining which characteristics of IFIS are associated with the 


 
Protocol Template 
Page 3 
CF-146, Effective 7/10/11 
 
highest complication rates.  Previous attempts to solve the problem of 
small pupil size during examination and surgery have not yet showed 
promising results as they only improve pupil dilation modestly.  A 
solution not yet explored is to create a temporary, pharmacologically 
induced Horner’s Syndrome, resulting in the temporary upregulation of 
α-1 receptors on the iris.  This temporary upregulation of α-1 receptors 
would lead to moderate pupil constriction at rest, but in the presence of 
α-1 selective dilating drops such as phenylephrine, the result would be 
a “supersensitive” response and substantial pupil dilation in an eye that 
would otherwise not dilate adequately for surgical intervention.  
 
Through disease mimicry, our method uses topical α-2 agonists to 
create a pharmacological Horner’s Syndrome. Since activation of pre-
synaptic α-2 receptors activates the negative feedback mechanism, this 
treatment will decrease the release of norepinephrine (NE) into the 
synaptic cleft. The lack of NE in the synaptic cleft will upregulate the 
post-synaptic α-1 receptors on the iris dilator muscle, which in turn will 
result in supersensitivity to any topical α-1 receptor agonist such as 
phenylephrine or epinephrine: 
 
   
 
 
Our initial research shows promising results. Preliminary data collected 
in one healthy human showed that pre-treatment with brimonidine 


 
Protocol Template 
Page 4 
CF-146, Effective 7/10/11 
 
tartrate, a commercially available topical α-2 agonist prescribed for 
glaucoma treatment, resulted in increased dilation when compared to 
the non-treated eye. Specifically, after 4 days of pre-treatment with 
brimonidine in only one eye, the brimonidine-treated eye had an 84.4% 
greater surgical working area compared to the non-treated eye 
(11.16mm2 vs 20.59mm2).  
 
A preliminary IRB-approved study is currently under way looking at 
pupil dilation in patients with Horner’s Syndrome who have previously 
been on a systemic α-1 blocker.  This study titled “Exploration of Pupil 
Dilation in Horner's Patients Taking Flomax” studies the 
hypersensitivity that the effected Horner’s eye has to α-1 receptor 
agonists.   
 
Horner’s Syndrome represents the classical triad of unilateral miosis 
(pupil constriction) and anisocoria (asymmetric pupil size), ptosis 
(abnormal low-lying upper eyelid), and anhidrosis (loss of sweating 
ability).   This unilateral syndrome results from the destruction of 
autonomic sympathetic nerve axons leading to the loss of sympathetic 
innervation to one of the eyes and surrounding skin and subsequently, 
supersensitivity to α agonists (such as norepinephrine). This 
supersensitive state can be described through the Law of Denervation 
Supersensitivity (Cannon’s law) first described in 1939.   Specifically, 
for the eye, the iris is covered in α-1 and α-2 receptors.   These 
receptors result in pupil dilation via the bonding to the sympathetic 
neurotransmitter norepinephrine.  In a normal physiologic state, there is 
a set level of norepinephrine released that serves to keep the 
population of α-1 receptors at a normal level.  In Horner’s Syndrome, 
however, there is a lack of norepinephrine release secondary to the 
denervation upstream from the iris. The absence of the sympathetic 
neurotransmitters in Horner’s syndrome results in an upregulation of 
alpha receptors onto the muscle fibers responsible for pupil dilation.  
The increased number of alpha receptors on the iris is responsible for 
the supersensitive state that results in an exaggerated dilation of the 
pupil.     
 
The final results of this ongoing study will serve as the proof of concept study to 
evaluate how pharmacologic mimicry of an induced Horner’s state for the eye may 
result in the ability to offset poor pupil dilation in patients with IFIS. 
 
IV. Research Methods 
 
A.  Outcome Measure(s):   
The primary hypothesis for this study is that application of routine dilating 
medications (Phenylephrine Hydrochloride 10%, tropicamide 1%, and 


 
Protocol Template 
Page 5 
CF-146, Effective 7/10/11 
 
cyclopentolate 1% ophthalmic solutions) will dilate the brimonidine tartrate pre-
treated eye more than the non-treated eye in patients previously treated with 
tamsulosin.  
 
The primary outcome measure for this single arm study is pupil diameter size post 
dilation (using standard dilating medications of phenylephrine 10%, tropicamide 
1%, and cyclopentolate 1%) of the brimonidine tartrate pre-treated eye compared 
to the non-treated eye.  
 
The secondary outcome is the change in pupil diameter of each eye after dilation 
at the start of the study, compared to pupil post dilating drops at the end of the 
study.   
 
B. Description of Population to be Enrolled:   
This study will recruit from the Denver Health Medical Center Eye Clinic.  Adult 
subjects who have any history of taking tamsulosin and do not meet one of the 
exclusion criteria will be approached for consent. .Adult patients must be able 
to consent for study participation by themselves.  Exclusion criteria that will 
eliminate potential subjects for enrollment includes: 
1) Subjects with untreated hypertension, baseline BP >160 
2) Subjects with thyrotoxicosis 
3) Pregnant women 
4) Prisoners 
5) Inability to consent 
6) Subjects with anatomical narrow angles who have never had a 
dilated exam 
7) Subjects currently prescribed brimonidine tartrate for glaucoma  
8) Subjects who require topical or systemic α agonists  
9) Any eye disease that would alter pupil dilation 
 
C. Study Design and Research Methods   
Single Arm, Superiority Trial  
 
This is a single arm study. All enrolled subjects will receive the interventional drug, 
Brimonidine tartrate 0.2%, to be applied to ONE eye only.  Brimonidine is currently 
an FDA approved drug with a favorable safety profile, thus an internal pilot efficacy 
trial is the next step to evaluate the off-label use of Brimonidine to treat IFIS.  The 
internal pilot (i.e., pilot data are part of the final sample size) data will be used to 
improve the estimation of variance in response to these medications, since the 
therapy approach is novel and there are no published data. In addition, the internal 
pilot will be used to re-assess recruitment methods, as well as patient satisfaction 
and adherence.    
 
This study will investigate the resulting difference in pupil dilation in the treated eye 
(Brimonidine Tartrate .2% for 7 days) eye compared to the non treated eye. The 


 
Protocol Template 
Page 6 
CF-146, Effective 7/10/11 
 
investigators hypothesize that in patients with IFIS, brimonidine tartrate .2% is 
superior to the current standard of care for pupil dilation for surgical preparation.   
 
The primary outcome is pupil dilation sized of the treated eye compared to the 
non-treated eye, and the secondary outcome is pupil dilation of the treated eye 
compared to the pre-treatment pupil dilation size of that same eye.  
 
Patients will be screened at their annual Denver Health Eye Clinic examination.  
Clinical examinations will involve a medication history and baseline vitals, as per 
standard of care, and any patient taking a systemic α blocker (such as tamsulosin) 
will be approached for consent if they do not meet any exclusion criteria.  
 
For all patients, consent will occur in person in the Denver Health Eye Clinic in a 
private setting at the first study visit, or at a standard of care visit which will include 
study procedures.  Consent will be obtained by a member of the research team.  
Once consent has occurred, the principal investigator (PI) will examine the 
patient’s anterior eye segment and measure the subject’s pupil diameter prior to 
instilling the dilating drops.  Pupil measurements will occur with the use of a Digital 
Pupillometer (NeuroOptics Inc, Irvine, California, USA).  The Digital Pupillometer 
measures objective pupil size and reactivity data independent of the examiner and 
allows changes in pupil reactivity to be trended over time.   
 
The PI will then instill the pupil dilation drops using the pre-operative dilating 
cocktail given in the pre-operative phase of cataract surgery.  The dilating cocktail 
is composed of phenylephrine 10%, tropicamide 1%, and cyclopentolate 1% 
drops.   All of these drugs have a well known safety profile and thus we expect 
minimal side effects during this clinical trial.  Measurement for post dilation pupil 
size will occur at 15, 30, and 45 minutes after instillation of these medications.  
After the pupil measurement with the pupillometer, the study related activity for the 
initial visit will be complete.  If patients are in the clinic for their regular 
examination, the clinic specialists will commence the exam at that time.   
 
After this initial visit, a 20-day washout period will ensue.  During this time, the 
patient will be asked to not use any topical or systemic α-agonists.   They may 
continue to use systemic α-receptor blockers such as tamsulosin.  After this 20-
day washout period, patients will begin treatment using brimonidine tartrate 0.2% 
three (3) times per day in the right eye.  This dose and frequency is the FDA 
approved dose for glaucoma patients, and at this dose the side effect profile is well 
tolerated.   
 
After 7 days of treatment, the patient will return to the Denver Health Eye Clinic.  
Again, the PI will examine the patient’s anterior eye segment and measure the 
subject’s pupil diameter prior to instilling dilating drops.  Pupil measurements will 
occur with the use of the NeurOptics Digital Pupillometer. After measurement of 
both pupils in the clinical examination room, the routine eye drop cocktail for 


 
Protocol Template 
Page 7 
CF-146, Effective 7/10/11 
 
dilation prior to cataract surgery (phenylephrine 10%, tropicamide 1%, and 
cyclopentolate 1% drops) will be placed on both of the subject’s eyes by the PI. 
Measurement post dilation will occur 15, 30 and 45 minutes after instillation of 
these medications.   After the pupil measurement with the pupillometer, the study 
related activity will be complete.   
 
Schedule of Events 
 
Baseline 
Visit, Day 0 
Week 1,  
Days 1-7 
Week 2 
Days 8-14 
Week 3,  
Days 15-21 
Week 4, 
Days 22-28 
Final Visit, 
Day 29 
Screening 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
X 
Anterior Eye Exam 
X 
 
 
 
 
X 
Pre-Dilation Pupil 
Measurements 
X 
 
 
 
 
X 
Dilating Cocktail 
X 
 
 
 
 
X 
Post-Dilation Pupil 
Measurements 
X 
 
 
 
 
X 
Washout Period 
 
X 
X 
X 
 
 
Brimonidine Tartrate 
.2% TID, Right Eye 
 
 
 
 
X 
 
Side Effect 
Questionnaire 
 
 
 
 
 
X 
 
 
All subjects will be paid for their participation in this study.  A ClinCard with $25 will 
be distributed to each subject after each one of the two visits as reimbursement for 
their time and travel, for a total of $50 for study duration.  
 
 
D.   Description, Risks and Justification of Procedures and Data 
Collection Tools: 
 
Risks to Subjects: 
Brimonidine Tartrate will be prescribed for 7 days TID at the FDA approved dose 
for glaucoma.  There are some risks associated with this drug, but it is a very well 
tolerated topical medication approved for long term use: 
• Most common side effects associated with this medication (10-30%), in 
descending order: oral dryness, ocular hyperemia, burning adn stinging, 
headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival 
follicles, ocular allergic reactions, ocular pruritus.  
• Less common side effects (3-9%) of patients: corneal straining/erosion, 
photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, 
upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, 
blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, 
conjunctival blanching, abnormal vision and muscular pain 


 
Protocol Template 
Page 8 
CF-146, Effective 7/10/11 
 
• Adverse reactions that were reported in less than 3% of patients: lid 
crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival 
discharge, depression, hypertension, anxiety, palpitations/arrhythmias, 
nasal dryness and syncope 
• Post-marketing side effects reported (unknown frequency): bradycardia, 
hypotension, iritis, miosis, skin reactions (including erythema, eyelid puritis, 
rash, and vasodilation), tachycardia, apnea, bradycardia, hypotension, 
hypothermia, hypotonia, and somnolence. 
  
The other drugs included in the protocol will be applied twice, 21 days apart, by 
the PI only; the following side effects have been reported in these drugs, but 
frequency are not listed.  
 
• Side effects of Phenylephrine 10% (not in known frequency order):   pre-
existing cardiovascular disease with use of phenylephrine 10% can result in 
serious adverse reactions.  Other more common, but less serious side 
effects: rebound miosis, elevation in blood pressure, eye pain, stinging, 
temporary blured vision, photophobia, conjunctival sensitivity 
 
• Side effects of cyclopentate 1%: increased intraocular pressure, burning, 
photophobia, blurred vision, irritation, hyperemia, conjunctivities, 
blepharoconjunctivitis, punctate keratitis, synechiae 
 
• Side effects of tropicamide 1%: transient stinging, blurred vision, 
photophobia and superficial keratitis; increased intraocular pressure; 
dryness of the mouth, tachycardia, headache, allergic reactions, nausea, 
vomiting, pallor, central nervous system, disturbances, and muscle rigidity 
 
The PI will monitor for side effects at study visits and all side effects will be 
captured for data analysis.  Any serious adverse events will be reported to 
COMIRB. 
 
Data Collection: 
The pupil measurements will be stored in a private, password protected Excel 
database for this study.  This database will contain patient’s name, MRN, age, sex, 
past medical history, and current medications, along with the each pupil 
measurements in time (for a total of 8 pupil measurements).  The PHI from this 
database will be deleted after the study concludes, but the pupillometer readings 
will remain paired with de-identified medical data.  
 
We are seeking Investigational New Drug (IND) application exemption for 
brimonidine tartrate 0.2% for the following reasons: 
 


 
Protocol Template 
Page 9 
CF-146, Effective 7/10/11 
 
1. Brimonidine tartrate 0.2% is an α adrenergic agonist lawfully marketed 
in the United States indicated for lowering intraocular pressure (IOP) in 
patients with open angle glaucoma or ocular hypertension.  
2. The investigation is not intended to be reported to the FDA as a well-
controlled study in support of a new indication for use of the drug 
product. 
3. The investigation is not intended to support a significant change in 
advertising to an existing lawfully marketed prescription drug product. 
4. The investigation does not involve a route of administration or dosage 
level or use in a patient population or other factor that significantly 
increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug product. Dosage and administration 
in this study will be exactly the same as is indicated and FDA approved 
for open angle glaucoma or ocular hypertension: “One drop in the 
affected eye(s), three times daily, approximately 8 hours apart”.  
Furthermore, we will only be using this medication for 7 days.  This is far 
shorter of a treatment course than is typically used.  Typically, this 
medication is used continuously for many years/decades to treat the 
above eye conditions.  
5. The investigation will be conducted in compliance with the requirements 
for institutional review set forth in FDA regulations 21 CFR 56, and 
requirements for informed consent as set forth in FDA regulations 21 
CFR 50.  We are seeking IRB approval for this study and all patients 
must give consent in order to enroll. 
6. The investigation will be conducted in compliance with FDA regulations 
21 CFR 312.7: Promotion and charging for investigational drugs. We will 
not represent the off-label use of the drug for this study as safe and 
effective or otherwise promote it. The medication used in this study will 
be obtained and paid for by the investigator, and will not be charged to 
the subject or subject's insurance. 
 
F.   Data Analysis Plan:   
 
Cases and Controls: Each treated eye (Case) has two Controls: 1) the baseline 
measurement of the treated eye prior to commencing pre-treatment and 2) the left, 
untreated eye after pre-treatment is completed. The two controls (baseline and 
untreated eye) are necessary to assess the possible role of systemic effects of the 
α-2 agonist (which could affect the untreated eye).   Our primary and secondary 
endpoints are the change in pupil diameter of the treated right eye compared to 
the pre-treated pupil dilation size, and compared to the untreated left eye pupil 
dilation size.   
 
Tertiary endpoints are noted side effects from the administration of topical 
brimonidine tartrate .2% TID for 7 days. Brimonidine tartrate has a well tolerated 
side effect profile, so at a shortened duration of 7 days we expect minimal 


 
Protocol Template 
Page 10 
CF-146, Effective 7/10/11 
 
systemic effects by teaching the patients specific procedures (punctal occlusion) 
during drop instillation to minimize systemic effects. 
 
Assumptions for sample size: All calculations assume two-tailed tests, with 80% 
power and 95% confidence. The overall sample size is initially calculated based on 
published data on healthy volunteers and patients on tamsulosin. After 50% 
enrollment in each arm, we will re-calculate the variance based on acquired data 
and re-estimate the final sample size.8 This initial comparison will be considered 
as an interim look using the O’Brien-Fleming alpha spending function. All samples 
size calculations will be conducted using PASS Power Analysis and Sample Size 
Software (2015, NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass). 
Based on Theodossiadis et al. (2), normal individuals show a 2.9 ± 0.5 (standard 
deviation) fold change in pupil minimum aperture after phenylephrine 10% 
compared to 2.7 ± 0.5 (standard deviation) fold change in patients taking 
tamsulosin for >=6 months. It should be noted that even minimal increases in pupil 
aperture result in large, clinically relevant improvements in the surgical field. With 
the above assumptions, maintaining a worst case scenario of a standard deviation 
of 0.45,  and 30% attrition rate, 30 patients will be needed to detect a minimum 
difference in pupil aperture fold change of 0.3 (effect size=0.6).   
 
G.  Summarize Knowledge to be Gained:   
BPH is the most commonly diagnosed condition for male patients age 45-74.9 It is 
estimated that up to 90% of men between the age of 45 and 90 suffer from BPH.10 
The most common and effective treatment, recommended as first line therapy for 
BPH by the American Urological Association, is the selective α-1 blocker (e.g.: 
tamsulosin) that target α-1 receptors in the genitourinary (GU) system. The risk of 
IFIS among men taking tamsulosin was as high as 90% in 10 retrospective and 
prospective studies. 
 
The scope of the unmet clinical need is staggering. 3.6 million cataract surgeries 
are performed each year in the USA alone, 20 million worldwide. An estimated 2% 
of these surgeries have IFIS (72,000 cases each year in the USA).1 The cataract 
and BPH population is only expected to increase over the next 30 years due to 
population aging.11 
 
This study will provide data on the potential treatment of IFIS. Currently no 
adequate treatment for IFIS exists. This potential treatment method creates a 
“pharmacologically induced Horner’s Syndrome”, resulting in an increased 
response to mydriatic medications.  This is accomplished by blocking the 
sympathetic innervation, whseraich upregulates α-1 receptors on the iris. This 
supersensitivity to dilating medications counteracts the poor dilation that 
tamsulosin causes.  
 
In the face of population growth and increasing IFIS prevalence, this could be a 
novel therapy in the fight against IFIS-related surgical complications. 


 
Protocol Template 
Page 11 
CF-146, Effective 7/10/11 
 
 
 H. References: 
 
1. Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated 
with tamsulosin. J Cataract Refract Surg 2005; 31:664–673. 
2. Lim LA, Frost A. Iris tears secondary to intraoperative floppy-iris syndrome 
associated with tamsulosin. J Cataract Refract Surg 2006; 32:1777. 
3. Storr-Paulsen A, Jorgensen JS, Norregaard JC, Thulesen J. Corneal 
endothelial cell changes after cataract surgery in patients on systemic 
sympathetic alpha-1a antagonist medication (tamsulosin). Acta Ophthalmol 
2014; 92:359–363. 
4. Ryburn C, Lynch AM, Patnaik JL, Cathcart J, Alexander J, Davidson RS, 
Taravella MJ. The Financial Burden of Posterior Capsular Rupture (PCR) in 
America. Presentation. American Society of Cataract and Refractive 
Surgery Annual Meeting 2018. April 15, 2018. 
5. Flach AJ. Intraoperative floppy iris syndrome: pathophysiology, prevention, 
and treatment. Transactions of the American Ophthalmological Society. 
2009 Dec;107:234. 
6. Chang, D.F., Osher, R.H., Wang, L. and Koch, D.D., 2007. Prospective 
multicenter evaluation of cataract surgery in patients taking tamsulosin 
(Flomax). Ophthalmology, 114(5), pp.957-964. 
7. Theodossiadis PG, Achtsidis V, Theodoropoulou S, Tentolouris 
N, Komninos C, FountasKN. The effect of alpha antagonists on pupil 
dynamics: implications for the diagnosis of intraoperative floppy iris 
syndrome. American journal of ophthalmology, 153(4), pp.620-622 
8. Billingham SAM, Whitehead AL, Julious SA. An audit of sample sizes for 
pilot and feasibility trials being undertaken in the United Kingdom registered 
in the United Kingdom Clinical Research Network database. BMC Med Res 
Methodol. 2013;13(1):104. 
9. Isaa MM, Marshall FF. Contemporary Diagnosis and Management of 
Disease of the Prostate. Newton, Pa: Handbooks in Healthcare Co.;200. 
10. McVary KTet al. Update on AUA guideline on the management of benign 
prostatic hyperplasia. J Urol. 2011 May;185(5):1793-803. 
11. Manvikar S, Allen D. Cataract surgery management in patients taking 
tamsulosin staged approach. J Cataract Refract Surg 2006; 32:1611–1614. 
 
 
 
 
 

ICF_003.pdf: 
Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 9-29-15
Page 1 of 7
Principal Investigator:
Dr. Cristos Ifantides
COMIRB No: 18-1713
Version Date:  02/22/2019
Study Title:  Enhanced Pupil Dilation in Patients Taking Alpha-Blockers for 
Potential Treatment of Intraoperative Floppy Iris Syndrome
You are being asked to be in a research study.  This form provides you with information 
about the study. A member of the research team will describe this study to you and 
answer all of your questions. Please read the information below and ask questions 
about anything you don’t understand before deciding whether or not to take part. 
Why is this study being done?
This study plans to learn more about the ability of Brimonidine, a topical alpha agonist 
medication, to treat Intraoperative Floppy Iris Syndrome..  Intraoperative Floppy Iris 
Syndrome (IFIS) causes poor pupil dilation and most often occurs in patients who take 
medication for BPH, such as Tamsulosin.  IFIS results in increased risk of of 
complications during eye surgery. .  
You are being asked to be in this research study because you have been prescribed 
Tamsulosin (Flomax) or another medication similar to it (an alpha blocker)  at 
some point in your life and this puts you at increased risk for having IFIS, which 
would be diagnosed during eye surgery. 
Other people in this study
Up to 30 people from your area will participate in the study. 
What happens if I join this study?
If you join the study, you will be asked to come to Denver Health Eye Clinic for a 
pupil examination and then pupil dilation with the standard pre-operative pupil 
dilation medications.  The investigator will measure your pupil size before instilling 
the drops, and then 15, 25-30, and 45 minutes after instilling the drops.  
While the dilation effects of these drops are usually subsided after 24 hours, we will 
wait 3 weeks before prescribing the next medication.  
COMIRB
APPROVED
For Use
01-Nov-2019
31-Oct-2020


Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 9-29-15
Page 2 of 7
At 3 weeks into study participation we will prescribe you Brimonidine Tartrate .2% to 
be applied to your RIGHT eye 3 times each day for a total of 7 days.The investigator 
will show you how to properly put these drops in your right eye.  This will dilate the 
pupil of this eye for the entire 7 days. 
Once you complete all 7 days of eye drops to the right eye, you will return to the eye 
clinic for pupil dilation a gain.  The investigator will measure your pupil size, instill the 
dilating drops, and then re-measure post-dilation pupil size.  
No procedures done in this study are done as part of your routine eye care.  All 
study procedures are research related only. 
Optional Additional Study Procedures: 
If you would like to be contacted for future research opportunities, the investigator 
would like to add your name and contact information to a “potential future study 
database”.  This database will be maintained by the study PI, and only he will have 
access to your information for contacting for future studies. 
Please select your choice:
☐ Yes, Please add my name and contact information to the Future Research 
Database  
☐No I do not want to be contacted for future research 
What are the possible discomforts or risks?
Discomforts you may experience while applying brimonidine tartrate .2% for 7 days 
include transient burning, stinging, itchiness, dryness, or other eye irritations.  You 
may also develop swelling around the eye or eyelid, red eye, eye tearing, visual 
disturbances.  Other temporary side effects that have been reported include 
systemic symptoms such as stomach aches, diarrhea, constipation, fatigue or 
increased tiredness, increased sadness/depression, or decreased sleep/insomnia.    
During the study visits when you are given the dilating compound composed of 
cyclopentate 1%, tropicamide 1%, and phenylephrine 1%, you may experience 
transient burning, stinging, irritation, and visual disturbances.  This medication may 
also cause temporary headache, dry mouth, red eye, increased heart rate of blood 
pressure.  
There is a risk that people outside of the research team will see your research 
information.  We will do all that we can to protect your information, but it can not be 
guaranteed.


Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 9-29-15
Page 3 of 7
If you become pregnant, the particular treatment or procedures involved in the study 
may involve risks to the embryo or fetus which are currently unclear.  Treatment 
should be stopped. 
The study may include risks that are unknown at this time. 
What are the possible benefits of the study? 
This study is designed for the researcher to learn more about brimonidine tartrate’s 
ability to treat IFIS compared to the current standard of care.  This study is not 
designed to treat any illness or to improve your health.  Also, there may be risks, as 
discussed in the section describing the discomforts or risks.   
Will I be paid for being in the study?  
You will be paid $50.00 for each visit in this study.  This will add up to a total of 
$100.00 if you complete all of the visits  If you leave the study early, or if we have to 
take you out of the study, you will be paid only for the visits you have completed.
It is important to know that payments for participation in a study is taxable income. 
Payments for taking part in this research study will be put onto a “ClinCard”.  ClinCard is 
managed by a company named Greenphire.  ClinCard works like a gift card and can be 
redeemed where Mastercard is accepted. At a minimum, your name, date of birth and 
social security number will be given to Greenphire in order for study payments to be 
loaded onto a ClinCard.  Let the research staff know if you have concerns about using 
ClinCard.
It is important to know that payments for participation in a study is taxable income. If you 
receive $600 or more from Denver Health & Hospital Authority in one tax year, you will 
be sent an IRS Form 1099 for tax purposes.
Will I have to pay for anything?
We will provide the study drug at no cost during this study.  Tests and procedures that 
are done only for the study will not be billed to you or your insurance company.  
You or your insurance company may be billed for:

Any standard medical care given during this research study.
You may want to talk with your insurance company about its payment policy for 
standard medical care given during a research study.  If your insurance company does 
not pay, you may be billed for those charges.
You might have unexpected expenses from being in this study.  Ask your study doctor 
to discuss the costs that will or will not be covered by the sponsor.  This discussion 
should include who will pay the costs of treating possible side effects.


Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 9-29-15
Page 4 of 7
Is my participation voluntary?
Taking part in this study is voluntary.  You have the right to choose not to take part in 
this study.  If you choose to take part, you have the right to stop at any time.  If you 
refuse or decide to withdraw later, you will not lose any benefits or rights to which 
you are entitled. 
Can I be removed from this study? 
The study doctor may decide to stop your participation without your permission if the 
study doctor thinks that being in the study may cause you harm, or for any other 
reason. 
What happens if I am injured or hurt during the study? 
If you have an injury while you are in this study, you should call Dr. Ifantides 
immediately.  His phone number is (303) 436-4949.
We will arrange to get you medical care if you have an injury that is caused by this 
research.  However, you or your insurance company will have to pay for that care. 
Who do I call if I have questions?
The researcher carrying out this study is Dr. Cristos Ifantides. You may ask any 
questions you have now. If you have questions, concerns, or complaints later, you 
may call Dr. Ifantides at (303) 436-4949. You will be given a copy of this form to keep.  
You may have questions about your rights as someone in this study. You can call Dr. 
Ifantides with questions.  You can also call the responsible Institutional Review Board 
(COMIRB).  You can call them at 303-724-1055. 
A description of this clinical trial will be available on http://www.Clinical Trials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this Web 
site at any time.
Who will see my research information?
The University of Colorado Denver (UCD) and its affiliated  hospital(s)  have rules to 
protect information about you.  
Federal and state laws including the Health 
Insurance Portability and Accountability Act (HIPAA) also protect your privacy.   This 
part of the consent form tells you what information about you may be collected in this 
study and who might see or use it.  


Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 9-29-15
Page 5 of 7
The institutions involved in this study include 
University of Colorado Denver
Denver Health 
We cannot do this study without your permission to see, use and give out your 
information.  You do not have to give us this permission.  If you do not, then you may 
not join this study.  
We will see, use and disclose your information only as described in this form and in 
our Notice of Privacy Practices; however, people outside the UCD and its affiliate 
hospitals may not be covered by this obligation.
We will do everything we can to maintain the confidentiality of your personal 
information but confidentiality cannot be guaranteed. 
The use and disclosure of your information has no time limit.  You can cancel your 
permission to use and disclose your information at any time by writing to the study’s 
Principal Investigator (PI), at the name and address listed below.  If you do cancel 
your permission to use and disclose your information, your part in this study will end 
and no further information about you will be collected.  Your cancellation would not 
affect information already collected in this study.  
Cristos Ifantides, MD, MBA
700 Delaware St
Pavillion D
Denver, CO 80204
Both the research records that identify you and the consent form signed by you may 
be looked at by others who have a legal right to see that information, such as:.  

Federal offices such as the Food and Drug Administration (FDA) and the Office 
of Human Research Protections (OHRP) that protect research subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB)

The study doctor and the rest of the study team.

Officials at the institution where the research is conducted and officials at other 
institutions involved in this study who are in charge of making sure that we follow 
all of the rules for research
We might talk about this research study at meetings.  We might also print the results 
of this research study in relevant journals.  But we will always keep the names of the 
research subjects, like you, private. 


Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 9-29-15
Page 6 of 7
You have the right to request access to your personal health information from the 
Investigator. [To ensure proper evaluation of test results, your access to these study 
results may not be allowed until after the study is completed]. 
Information about you that will be seen, collected, used and disclosed in this 
study:

Name and Demographic Information (age, sex, ethnicity)

Portions of your previous and current Medical Records that are relevant to this 
study, including but not limited to Diagnosis(es), History and Physical

Research Visit and Research Test records
HIPAA Authorization for Optional Additional Study Procedures 
In this form, you  were given the option to agree to additional, optional research 
procedures.  You must also give us your permission, under HIPAA rules, to use and 
disclose the information collected from these optional procedures, as described 
above.  
If you decline to give us permission to use and disclose your information, you cannot 
take part in these optional procedures, but you can still participate in the main study.  
Please initial next to your choice:
_____ I give permission for my information, from the optional procedures I have 
agreed to above, to be used and disclosed as described in this section.
_____ I do not give permission for my information for any optional procedures to be 
used and disclosed; I understand that I will not participate in any optional 
procedures.


Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 9-29-15
Page 7 of 7
Agreement to be in this study and use my data
I have read this paper about the study or it was read to me.  I understand the possible 
risks and benefits of this study.  I understand and authorize the access, use and 
disclosure of my information as stated in this form.  I know that being in this study is 
voluntary.  I choose to be in this study: I will get a signed and dated copy of this consent 
form.
Signature:
Date:
Print Name:
Consent form explained by:
Date:
Print Name: