The Role of Topical Antibiotic Prophylaxis in Eyelid Surgery
Phase: PHASE4
Conditions: Antibiotic Side Effect, Eyelid; Wound, Eyelid Diseases, Surgical Wound Infection, Surgical Wound, Recent, Surgical Incision, Skin Cancer Face, Antibiotic Allergy, Surgical Site Infection
Sponsor: University of California, San Francisco

Title: THE ROLE OF TOPICAL ANTIBIOTIC PROPHYLAXIS IN EYELID 
SURGERY 
NCT Number: NCT03199911 
Date: 9/9/2018 

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UNIVERSITY OF CALIFORNIA, SAN FRANCISCO 
Clinical Research Protocol 
THE ROLE OF TOPICAL ANTIBIOTIC PROPHYLAXIS IN EYELID SURGERY 
Protocol Number: 
17-22309 
Version Date: 
9/9/2018 
Investigational Product: Topical Antibiotic Ointment 
IND Number: 
N/a 
Development Phase: 
 
Sponsor: 
Name: Dr. Robert Kersten  
 
Telephone: (415) 353-2142 
 
Fax: (415) 514–6034 
 
 
E-mail: 
 Robert.kersten@ucsf.edu  
Funding Organization: 
N/a 
Principal Investigator: 
Name: Dr. Robert Kersten  
 
Telephone: (415) 353-2142 
 
Fax: (415) 514–6034 
 
 
E-mail: 
 Robert.kersten@ucsf.edu  
Medical Monitor: 
Data Safety and Monitoring Committee (DSMC): 
Dr. John Gonzales 
Dr. Jeremy Keenan 
Dr. Gerami Seitzman 
Telephone:  415-476-6323 
E-mail: 
 jeremy.keenan@ucsf.edu  
Coordinating Center: 
N/a 
 
Approval: 
 
 
 
 
 
 
 
 
 
 
 

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9/9/18 
PI or Sponsor Signature (Name and Title)  
 
 
 
 
Date 
This confidential information about an investigational product is provided 
for the exclusive use of investigators of this product and is subject to recall 
at any time.  The information in this document may not be disclosed unless 
federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons 
involved in the study who have a need to know, with the obligation not to 
further disseminate this information.   

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my 
duties include ensuring the safety of the study subjects enrolled under my 
supervision and providing Dr. Robert Kersten with complete and timely information, 
as outlined in the protocol.  It is understood that all information pertaining to the 
study will be held strictly confidential and that this confidentiality requirement 
applies to all study staff at this site. Furthermore, on behalf of the study staff and 
myself, I agree to maintain the procedures required to carry out the study in 
accordance with accepted GCP principles and to abide by the terms of this 
protocol. 
 
Protocol Number:  17-22309 
 
Protocol Title: The Role of Topical Antibiotic Prophylaxis in Eyelid Surgery  
 
Protocol Date:  9/9/18  
 
 
 
9/9/18 
Investigator Signature  
 
Date 
Robert Kersten, MD  
Print Name and Title 
Site # 
1 
 
Site Name 
Parnassus 
Address 
400 Parnassus Ave, San Francisco, CA 94143 
Phone 
Number 
(415) 353-2142 
 

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TABLE OF CONTENTS 
 
1. 
Background and Rationale ...................................................................10 
2. 
Study Objectives  ..................................................................................11 
3. 
Study Design ........................................................................................11 
4. 
Criteria for Evaluation  ..........................................................................11 
5. 
Subject Selection  .................................................................................13 
6. 
Concurrent Medications  .......................................................................14 
7. 
Study Treatments .................................................................................14 
8. 
Study Procedures and Guidelines ........................................................15 
9. 
Evaluations by Visit  .............................................................................16 
10. Adverse Experience Reporting and Documentation  ............................17 
11. Discontinuation and Replacement of Subjects .....................................19  
12. Protocol Violations  ...............................................................................20 
13. Statistical Methods and Considerations  ...............................................21 
14. Data Collection, Retention, and Monitoring  .........................................22 
15. Administrative, Ethical, and Regulatory Considerations  ......................23 

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LIST OF ABBREVIATIONS 
AE 
adverse event 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
PI 
Principal Investigator 
SAE 
serious adverse experience 

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PROTOCOL SYNOPSIS 
TITLE 
The Role of Topical Antibiotic Prophylaxis in Eyelid Surgery 
SPONSOR 
UCSF 
FUNDING 
ORGANIZATION 
n/a 
NUMBER OF SITES 
1 
RATIONALE 
As antibiotic resistance, antibiotic-related complications (e.g. 
contact dermatitis), and healthcare costs are on the rise, the 
routine use of post-operative topical antibiotic prophylaxis 
should be examined. After all, the rates of postoperative 
infections involving Class I and Class II surgical wounds (as 
defined by the CDC, or Centers for Disease Control and 
Prevention), including those associated with eyelid surgery, are 
known to be low.  
Despite a lack of evidence supporting the use of prophylactic 
topical antibiotic therapy after eyelid surgery, the practice 
remains widespread both nationally and internationally. As 
such, we propose a randomized control trial testing the 
hypothesis that routine topical antibiotic prophylaxis does not 
significantly reduce the rate of infection after eyelid surgery. 
STUDY DESIGN 
This is a prospective randomized control trial. 
PRIMARY 
OBJECTIVE 
To determine if there is a role for topical prophylactic topical 
antibiotic therapy after eyelid surgery.  
SECONDARY 
OBJECTIVES 
To determine of rates of wound infection after eyelid surgery 
both with and without topical post-operative antibiotic 
prophylaxis; to determine if rates of wound infection after eyelid 
surgery are different among healthy and immunocompromised 
patients; to determine the type and frequency of adverse 
reactions resulting from topical antibiotic use.  
NUMBER OF 
SUBJECTS 
400 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
Patients aged 18 and older who are undergoing various eyelid 
procedures in an office, ambulatory care center, or operating 
room including but not limited to:  
• blepharoplasty (upper and lower lids);  
• ectropion repair;  

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• entropion repair;  
• external dacrocystorhinostomy;  
• external levator resection;  
• eyelid lesion removal and/or biopsy;  
• eyelid reconstruction and defect repair including after 
Mohs surgery;  
• fat pad excision (upper and lower lids);  
• gold or platinum weight implantation;  
• internal levator resection;  
• lateral tarsal strip;  
• orbital fracture repair requiring periorbital incisions;  
• orbitotomy requiring periorbital incisions;  
• tarsorrhaphy;  
• wedge excision.  
• Patients undergoing repeat procedures will also be 
included. 
 
Exclusion Criteria: 
• Patients aged younger than 18 years old who are 
undergoing the above eyelid procedures in an office, 
ambulatory care centers, operating rooms;  
• patients undergoing chalazion removal;  
• patients who have had previous wound infections at the 
site of the procedure;  
• patients with oral or IV antibiotic use within 10 days prior 
to procedure;  
• patients requiring IV antibiotics during the procedure;  
• patients with grossly contaminated or inflamed wounds;  
• patients with human or animal bites, 
• patients with wounds resulting from trauma 
• patients allergic to all study drug options. 
 
 

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TEST PRODUCT, 
DOSE, AND ROUTE 
OF ADMINISTRATION 
Topical Ophthalmic Antibiotic Ointment (e.g. poly-bacitracin, 
bacitracin). Apply a thin ribbon to surgical wounds 4 times a day 
(while awake) for 7 days. 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Artificial Tear Ointment (e.g. Refresh PM). Apply a thin ribbon 
to surgical wounds 4 times a day (while awake) for 7 days. 
DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF 
STUDY 
Subjects will be on study for up to 14 days.  
Screening:  During pre-operative assessment.  
Treatment Duration:  7 days 
Follow-up:  7-14 days 
The total duration of the study is expected to be 2 years with 
ongoing subject recruitment. Each subject will have a final 
follow-up at post-operative week 1 and/or post-operative week 
2 unless a post-operative infection occurs. In the event of a 
post-operative infection, final follow-up will occur upon infection 
resolution.  
CONCOMMITANT 
MEDICATIONS 
Allowed: All non-antimicrobial medications.  
 
Prohibited: Antibiotics taken by IV or by mouth.  
PRIMARY ENDPOINT 
• 
To determine the rates of eyelid surgical site infections 
(SSIs) with and without topical antibiotic therapy.  
SECONDARY 
ENDPOINTS 
• 
To determine the rate of eyelid SSIs in patients with 
compromised immune status (e.g. patients with diabetes, 
those who smoke, those on chronic high-dose steroids, etc.)  
• 
To classify the types of complications related to antibiotic 
ointment and artificial tear ointment use; to determine their 
respective rates. 
SAFETY 
EVALUATIONS 
Adverse events will reported according to the UCSF IRB 
reporting requirements. Risks of participating in this study are 
not greater than the risks involved in current post-operative 
standard of care regimens.  
PLANNED INTERIM 
ANALYSES  
Serious adverse events will be monitored on an ongoing basis 
throughout the study. Study data from each subsequent set of 
25 patients enrolled will be reviewed regularly by a Data Safety 
Monitoring Committee (DSMC).  

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STATISTICS 
Primary Analysis 
Plan 
We will plan to use a T-test or a linear regression model (with 
no covariates other than study arm). 
Rationale for Number 
of Subjects 
We aim to recruit 200 people for each arm of the study, totaling 
400 subjects. These numbers are commensurate to our regular 
surgical patient volume over the course of two years and as 
such, detected rates of infection will be clinically relevant.  
 

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1 
BACKGROUND AND RATIONALE  
Despite a lack of evidence supporting the use of routine topical antibiotic therapy 
(e.g. poly-bacitracin, bacitracin, erythromycin, etc.) after eyelid surgery, it is 
currently standard of care to provide patients with post-operative antibiotics in 
order to prevent surgical site infections (SSIs). For instance, a 2014 survey of 
oculoplastic surgeons from 43 countries revealed that while rates of prophylactic 
oral and perioperative intravenous antibiotic use varied considerably, topical 
antibiotic use was common across all geographic regions (85.2%).1  
The rates of postoperative infections involving Class I: Clean and Class II: Clean-
Contaminated* surgical wounds, including those associated with eyelid surgery, 
are known to be low. For instance, while the rate of infection after blepharoplasty is 
0.2% with antibiotic ointment use 2 and the rate of infection after external 
dacrocystorhinostomy is 1% with antibiotic use,3 the rates of infection without 
topical antibiotics in a range of dermatological procedures such as Mohs surgery 
are as low as 0.7%.4 There is currently no literature on the rates of infection after 
blepharoplasty and other eyelid-specific procedures in the absence of prophylactic 
antibiotic ointment.  
As antibiotic resistance, antibiotic-related complications (e.g. contact dermatitis), 
and healthcare costs are on the rise, it has been advocated that topical antibiotic 
prophylaxis be withheld in eyelid surgery except in certain high risk cases. As 
such, we propose a randomized control trial testing the hypothesis that routine 
topical antibiotic prophylaxis does not significantly reduce the rate of infection after 
eyelid surgery. The hope is to reduce rates of antibiotic resistance, antibiotic-
related complications, and healthcare costs.  
*Under CDC surgical wound classification system, Class I/Clean wounds include 
“an uninfected operative wound in which no inflammation is encountered and…[is] 
primarily closed and, if necessary, drained with closed drainage…Class II/Clean-
Contaminated wounds include those …without unusual contamination… [and] no 
evidence of infection or major break in technique.”  
1. Fay A, Nallasamy N, Bernardini F, et al. Multinational Comparison of Prophylactic Antibiotic 
Use for Eyelid Surgery. JAMA Ophthalmol. 2015 Jul; 133(7):778-84.  
2. Carter SR, Stewart JM, Khan J, et al. Infection after blepharoplasty with and without carbon 
dioxide laser resurfacing. Ophthalmology. 2003 Jul; 110(7):1430-2. 
3. Yazici B, Meyer DR. Selective antibiotic use to prevent postoperative wound infection after 
external dacryocystorhinostomy. Ophthal Plast Reconstr Surg. 2002; 18:331 
4. Saco M, Howe N, Nathoo R, et al. Topical antibiotic prophylaxis for prevention of surgical 
wound infections from dermatologic procedures: a systematic review and meta-analysis. J 
Dermatolog Treat. 2015 Apr; 26(2):151-8.  

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2 
STUDY OBJECTIVES 
2.1 Primary Objective 
The objective is to conclusively determine whether or not topical post-operative 
antibiotic use has a meaningful prophylactic role after eyelid surgery. 
2.2 Secondary Objectives 
To determine of rates of wound infection after eyelid surgery both with and without 
topical post-operative antibiotic prophylaxis; to determine if rates of wound 
infection after eyelid surgery are different among healthy and immunocompromised 
patients; to determine the type and frequency of adverse reactions resulting from 
topical antibiotic use. 
3 
STUDY DESIGN 
3.1 Study Overview 
This is a single center, placebo-controlled, randomized trial. 400 subjects are 
planned. Subjects will be randomly assigned to a study drug or to a placebo. Each 
subject will apply a single dose of topical study drug or placebo four times daily to 
their surgical wounds over the course of one week.  
Screening data will be reviewed to determine subject eligibility.  Subjects who meet 
all inclusion criteria and none of the exclusion criteria will be entered into the study.  
The following treatment regimens will be used: 
• 
Experimental treatment: topical ophthalmic antibiotic ointment (e.g. 
erythromycin, bacitracin or polybac)  
• 
Placebo: artificial tear ointment (e.g. Refresh PM) 
Total duration of subject participation will be from the time of approval for eyelid 
surgery to post-operative visit #1 (either one or two weeks after surgery). Total 
duration of the study is expected to be 2 years.  
4 
CRITERIA FOR EVALUATION 
4.1 Primary Efficacy Endpoint 
The primary endpoint will be the rate of superficial incisional and deep incisional 
surgical site infection (SSI) of clean and clean-contaminated wounds at 
postoperative visit week 1 and/or postoperative visit week 2. Superficial and deep 
incisional SSI will be defined per CDC surgical site infection criteria, slightly 
modified for the eyelid area, and will be evaluated by one of two observers (RV or 
RK):  
Modified Eyelid Superficial Incisional SSI:4  
(1) Infection occurs within 14 days after the operation,  
(2) AND infection involves only skin and subcutaneous tissue of the incision, 

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(3) AND at least one of the following criteria is met: 
• purulent drainage from the incision 
• organisms isolated from an aseptically obtained culture of fluid or tissue 
from the incision 
• at least one of the following signs or symptoms of infection: pain or 
tenderness, localized swelling, redness or heat  
• diagnosis of superficial incisional SSI by a surgeon or attending 
physician 
Modified Eyelid Deep Incisional Surgical Site Infection:4  
(1) Infection occurs within 14 days after the operation (or one year in case of 
implants) 
(2) AND infection involves deep soft tissues, such as the fascia and muscles,  
(3) AND at least one of the following criteria is met: 
• purulent drainage from the incision but not from the organ/space of the 
surgical site 
• a deep incision spontaneously dehisces or is deliberately opened by a 
surgeon when the patient has at least one of the following signs or 
symptoms: fever (>38°C), localized pain, or tenderness - unless the 
culture is negative 
• an abscess or other evidence of infection involving the incision is found 
on direct examination or by histopathologic or radiological examination 
• diagnosis of a deep incisional SSI by a surgeon or attending physician.  
 
 
5. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Hospital 
Infection Control Practices Advisory Committee. Guideline for prevention of 
surgical site infection, 1999. Infect Control Hosp Epidemiol. 1999; 
20(4):250–278. 
 
4.2 Secondary Efficacy Endpoints 
• 
The rate of superficial and deep SSI in high infection-risk groups such as 
patients with diabetes, those who smoke, those on chronic high-dose steroids, 
etc.  
• 
The classification of types of complications (e.g. allergic dermatitis) related to 
antibiotic ointment and artificial tear ointment use as well as their respective 
rates. 
4.3 Safety Evaluations 
• 
Adverse events will be monitored throughout the study and will be 
reported according to the UCSF IRB reporting requirements. 
• 
The DSMC will receive regular updates, including information such as: number 
of patients screened, number of participants enrolled, number of participants 
randomized/receiving treatment, number of participants lost to follow-up, 

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number of participants meeting the outcome definition, and number of 
participants with an adverse event. These updates will be made after each 
consecutive set of 25 participants has been enrolled. 
• 
Stopping rule for the trial: As part of the regular DSMC review process detailed 
above, the DSMC will make a determination at each review whether the study 
can continue.   
5 
SUBJECT SELECTION 
5.1 Study Population 
Subjects requiring or electing to undergo eyelid surgery and meet the inclusion 
criteria will be eligible for participation in this study.   
5.2 Inclusion Criteria 
Patients aged 18 and older who are undergoing various eyelid procedures in an 
office, ambulatory care center, or operating room including but not limited to:  
• blepharoplasty (upper and lower lids);  
• ectropion repair;  
• entropion repair;  
• external dacrocystorhinostomy;  
• external levator resection;  
• eyelid lesion removal and/or biopsy;  
• eyelid reconstruction and defect repair including after Mohs surgery;  
• fat pad excision (upper and lower lids);  
• gold or platinum weight implantation;  
• internal levator resection;  
• lateral tarsal strip;  
• orbital fracture repair requiring periorbital incisions;  
• orbitotomy requiring periorbital incisions;  
• tarsorrhaphy;  
• wedge excision.  
• Patients undergoing repeat procedures will also be included.  
• Written informed consent (and assent when applicable) obtained from 
subject or subject’s legal representative and ability for subject to comply 
with the requirements of the study. 
 
5.3 Exclusion Criteria 
• Patients aged younger than 18 years old who are undergoing the above 
eyelid procedures in an office, ambulatory care centers, operating rooms;  
• patients undergoing chalazion removal;  
• patients who have had previous wound infections at the site of the 
procedure;  
• patients with oral or IV antibiotic use within 10 days prior to procedure;  

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• patients requiring IV antibiotics during the procedure;  
• patients with grossly contaminated or inflamed wounds;  
• patients with human or animal bites, 
• patients with wounds resulting from trauma 
• patients who are allergic to all study drug options.   
6 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire 
study period, as medically feasible, with no introduction of new chronic therapies. 
The following medications are prohibited during the study and administration will 
be considered a protocol violation:  
• Intravenous antibiotics.  
• Oral antibiotics.  
7 
STUDY TREATMENTS 
7.1 Method of Assigning Subjects to Treatment Groups 
Patients will be randomly assigned to topical antibiotic ointment or placebo 
treatment groups in a 1:1 ratio using a computer-generated randomization scheme 
developed by the study statistician. Randomization will be performed at the time of 
study recruitment.  
7.2 Blinding 
Neither subjects nor investigators will be blinded.  
7.3 Formulation of Test and Control Products 
Test:  
Erythromycin Ophthalmic Ointment USP, 0.5%, 3.5g, Akorn 
OR  
Bacitracin Zinc Ophthalmic Ointment USP, 3.5g, Bausch+Lomb 
OR 
Bacitracin Zinc and Polymyxin B Sulfate Ophthalmic Ointment USP, 3.5g, Bausch 
+Lomb 
Control: 
Refresh PM Lubricant Eye Gel, 3.5g  
7.3.1 Packaging and Labeling 
Study drug will be supplied in single 3.5 g tubes and will be labeled per the 
manufacturer. 

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7.4 Supply of Study Drug at the Site 
Study drug supply (or placebo) will be obtained at an outpatient pharmacy on or 
before day of surgery.  
7.4.1 Dosage/Dosage Regimen 
Topical Ophthalmic Antibiotic Ointment (e.g. poly-bacitracin, bacitracin). Apply a 
thin ribbon to surgical wounds 4 times a day (while awake) for 7 days. 
OR 
Artificial Tear Ointment. Apply a thin ribbon to surgical wounds 4 times a day (while 
awake) for 7 days. 
7.4.2 Dispensing 
Study drug or placebo will be dispensed by an outpatient pharmacist.  
7.4.3 Administration Instructions  
See 7.4.1 
7.5 Supply of Study Drug at the Site 
n/a 
7.5.1 Storage 
n/a 
7.6 Study Drug Accountability 
n/a 
7.7 Measures of Treatment Compliance 
Subjects will be asked to keep a patient diary noting the day and date they take 
their study drug and any adverse events. They will be asked to bring their patient 
diary to each study visit along with all used and unused study drug containers. 
8 
STUDY PROCEDURES AND GUIDELINES 
Patients will be recruited at their pre-operative visits and be randomized to study 
drug vs placebo at that time (Visit 1). Study enrollment and randomization group 
will be recorded under the Apex smartphrase, “.RKRVEYELIDPRE” before being 
transferred to REDCap. Primary and secondary endpoints will assessed at 
postoperative week #1 (Visit 2) and recorded under the Apex smartphrase, 
“.RKRVEYELIDPOST” before being transferred to REDCap.  
Prior to conducting any study-related activities, written informed consent and the 
Health Insurance Portability and Accountability Act (HIPAA) authorization must be 
signed and dated by the subject or subject’s legal representative.  If appropriate, 
assent must also be obtained prior to conducting any study-related activities. 

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8.1 Clinical Assessments 
8.1.1 Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at Visit 1 
and 2 and at early termination when applicable.  Dose, route, unit frequency of 
administration, and indication for administration and dates of medication will be 
captured. 
8.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at Visit 1.  
8.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent 
respiratory history, and information regarding underlying diseases will be recorded 
at Visit 1.  
8.1.4 Physical Examination 
A complete eye examination will be performed by either the investigator or a 
subinvestigator who is a physician at Visit 1. New abnormal eye exam findings 
must be documented and will be followed by a physician or other qualified staff at 
the next scheduled visit. 
8.1.5 Adverse Events 
Information regarding occurrence of adverse events will be captured throughout 
the study. Duration (start and stop dates and times), severity/grade, outcome, 
treatment and relation to study drug will be recorded on the case report form 
(CRF). 
9 
EVALUATIONS BY VISIT 
9.1 Visit 1  
1. 
Review the study with the subject (subject’s legal representative) and obtain 
written informed consent and HIPAA authorization and assent, if appropriate. 
2. 
Record demographics data (e.g. age, sex, race). 
3. 
Record ophthalmologic and medical history, including current and recent 
antibiotic use.  
4. 
Perform eye exam.  
5. 
Randomize subject. 
6. 
Document randomization using Apex smartphrase, “.RKRVEYELIDPRE” 
7. 
Assign surgery date. 

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9.2 Visit 2 (Post-operative week 1) 
1. 
Record any Adverse Experiences and/or Review subject diary for adverse 
experiences and dosing compliance. 
2. 
Concomitant medications review. 
3. 
Perform abbreviated eye examination. 
4. 
Determine presence or absence of surgical site infection. 
5. 
Determine presence or absence of drug/placebo allergies.   
6. 
Determine if patient is immunocompromised.  
7. 
Start treatment if infection present. 
8. 
Document findings using Apex smartphase, “.RKRVEYELIDPOST”  
9.3 Visit 3 (Only if surgical site infection present at Visit 2.) 
1. 
Record any Adverse Experiences and/or Review subject diary for adverse 
experiences and dosing compliance. 
2. 
Record changes to concomitant medications. 
3. 
Perform abbreviated eye examination. 
4. 
Note duration of treatment and if infection resolved.  
9.4 Early Withdrawal Visit 
1. 
Record any Adverse Experiences and/or Review subject diary for adverse 
experiences and exclusionary medication use. 
2. 
Record changes to concomitant medications. 
3. 
Perform complete eye examination. 
10 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
10.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical 
investigation of a patient administered a pharmaceutical product and that does not 
necessarily have a causal relationship with the treatment.  An AE is therefore any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the administration of an 
investigational product, whether or not related to that investigational product.  An 
unexpected AE is one of a type not identified in nature, severity, or frequency in 
the current Investigator’s Brochure or of greater severity or frequency than 
expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of 
AEs during each subject visit and record the information in the site’s source 
documents.  Adverse events will be recorded in the patient CRF.  Adverse events 

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will be described by duration (start and stop dates and times), severity, outcome, 
treatment and relation to study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can 
be found in the study manual.  If the experience is not covered in the modified 
criteria, the guidelines shown in Table 1 below should be used to grade severity.  It 
should be pointed out that the term “severe” is a measure of intensity and that a 
severe AE is not necessarily serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may 
be aware of the sign or symptom but tolerates it 
reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal 
medical intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse 
experience as it occurred. This does not refer to an 
experience that hypothetically might have caused death if 
it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following 
the guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a 
reasonable temporal sequence from administration of the drug; that 
follows a known or expected response pattern to the suspected drug; 
that is confirmed by stopping or reducing the dosage of the drug; and 
that is not explained by any other reasonable hypothesis. 

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Probably 
An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or 
reducing the dosage of the drug; and that is unlikely to be explained by 
the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected response 
pattern to that suspected drug; but that could readily have been 
produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship 
to the study drug. 
10.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the 
following outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  
 
10.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) 
per UCSF CHR Guidelines.  The collection period for all SAEs will begin after 
informed consent is obtained and end after procedures for the final study visit have 
been completed. 
In accordance with the standard operating procedures and policies of the local 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC), the site 
investigator will report SAEs to the IRB/IEC.   
10.3 Medical Monitoring 
The DSMC will receive regular updates, including information such as: number of 
patients screened, number of participants enrolled, number of participants 
randomized/receiving treatment, number of participants lost to follow-up, number of 
participants meeting the outcome definition, and number of participants with an 
adverse event. These updates will be made after each consecutive set of 25 

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participants has been enrolled. As part of this regular review process, the DSMC 
will make a determination at each review whether the study can continue.   
Dr. Jeremy Keenan should be contacted directly at these numbers to report 
medical concerns or questions regarding safety. 
Phone: 415-476-6323 
11 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
11.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to 
continue.  The following is a list of possible reasons for study treatment 
discontinuation:  
• 
Subject withdrawal of consent (or assent) 
• 
Subject is not compliant with study procedures 
• 
Adverse event that in the opinion of the investigator would be in the best 
interest of the subject to discontinue study treatment 
• 
Protocol violation requiring discontinuation of study treatment 
• 
Lost to follow-up 
• 
Sponsor request for early termination of study 
If a subject is withdrawn from treatment due to an adverse event, the subject will 
be followed and treated by the Investigator until the abnormal parameter or 
symptom has resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early 
discontinuation visit as soon as possible and then should be encouraged to 
complete all remaining scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for 
subject withdrawals.  The reason for the subject’s withdrawal from the study will be 
specified in the subject’s source documents Refer to Section 9.4 for early 
termination procedures. 
11.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to 
continue.   
All subjects are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice. 

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Reasonable attempts will be made by the investigator to provide a reason for 
subject withdrawals.  The reason for the subject’s withdrawal from the study will be 
specified in the subject’s source documents.  As noted above, subjects who 
discontinue study treatment early (i.e., they withdraw prior to Visit 2) should have 
an early discontinuation visit. Refer to 9.4 for early termination procedures.   
11.3 Replacement of Subjects 
Subjects who withdraw from the study treatment will not be replaced.   
Subjects who withdraw from the study will not be replaced.   
 
12 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or Sponsor fails to 
adhere to significant protocol requirements affecting the inclusion, exclusion, 
subject safety and primary endpoint criteria.  Protocol violations for this study 
include, but are not limited to, the following: 
• 
Failure to meet inclusion/exclusion criteria 
• 
Use of a prohibited concomitant medication 
• 
Non-compliance with study drug regimen 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Sponsor will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a 
Protocol Violation Form detailing the violation will be generated. This form will be 
signed by a Sponsor representative and the Investigator. A copy of the form will be 
filed in the site’s regulatory binder and in the Sponsor’s files. 
13 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan 
(SAP) will be written describing all analyses that will be performed.  The SAP will 
contain any modifications to the analysis plan described below.   
13.1 Data Sets Analyzed 
All randomized subjects who have completed one week of study drug or placebo 
will be included in data analysis.  
All eligible patients who are randomized into the study and receive at least one 
dose of the study drug (the Safety Population) will be included in the safety 
analysis. 
13.2 Demographic and Baseline Characteristics 
Age  

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Gender  
Race  
Smoker (Y/N) 
13.3 Analysis of Primary Endpoint 
T-test or a linear regression model (with no covariates other than study arm). 
13.4 Analysis of Secondary Endpoints 
T-test or a linear regression model (with no covariates other than study arm). 
Adverse events will be tabulated by treatment group and will include the number of 
patients for whom the event occurred, the rate of occurrence, and the severity and 
relationship to study drug.   
13.5 Interim Analysis 
The DSMC will make determinations for interim analysis during their regular review 
of study data.  
13.6 Sample Size and Randomization 
200 patients will be randomized to the topical antibiotic group and 200 patients will 
be randomized to the artificial tear ointment group.  
 
14 DATA COLLECTION, RETENTION AND MONITORING 
14.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source 
documents designed to record all observations and other pertinent data for each 
subject treated with the study drug.   
 
Study personnel at each site will enter data from source documents corresponding 
to a subject’s visit into the protocol-specific electronic Case Report Form (eCRF) 
Subjects will not be identified by name in the study database or on any study 
documents to be collected by the Sponsor (or designee), but will be identified by a 
subject number and initials. 
For eCRFs: If a correction is required for an eCRF, the time and date stamps track 
the person entering or updating eCRF data and creates an electronic audit trail.   
The Investigator is responsible for all information collected on subjects enrolled in 
this study.  All data collected during the course of this study must be reviewed and 
verified for completeness and accuracy by the Investigator.  A copy of the CRF will 
remain at the Investigator’s site at the completion of the study. 

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14.2 Data Management Procedures 
The data will be entered into a validated database.  The Data Management group 
will be responsible for data processing, in accordance with procedural 
documentation.  Database lock will occur once quality assurance procedures have 
been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data 
for clinical trials. 
14.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized 
data validation checks will be implemented and applied to the database on a 
regular basis. Queries are entered, tracked, and resolved through the EDC system 
directly. The study database will be updated in accordance with the resolved 
queries.  All changes to the study database will be documented. 
14.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files 
will be maintained.  Databases are backed up by the database administrator in 
conjunction with any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final 
reports), data for analysis is locked and cleaned per established procedures. 
14.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency 
(e.g., FDA) inspectors upon request.  A file for each subject must be maintained 
that includes the signed Informed Consent, HIPAA Authorization and Assent Form 
and copies of all source documentation related to that subject.  The Investigator 
must ensure the reliability and availability of source documents from which the 
information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, 
Study File Notebook, etc.) must be kept secured for a period of two years following 
marketing of the investigational product or for two years after centers have been 
notified that the IND has been discontinued.  There may be other circumstances 
for which the Sponsor is required to maintain study records and, therefore, the 
Sponsor should be contacted prior to removing study records for any reason. 
14.6 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to 
the U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    
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designee), and appropriate regulatory authorities to conduct on-site monitoring 
and/or auditing of all appropriate study documentation. 
14.7 Subject Confidentiality 
In order to maintain subject confidentiality, only subject number and subject initials 
will identify all study subjects on CRFs and other documentation submitted to the 
Sponsor.  Additional subject confidentiality issues (if applicable) are covered in the 
Clinical Study Agreement. 
15 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and 
other records will be identified by a coded number and initials only.  All study 
records will be kept in a locked file cabinet and code sheets linking a patient’s 
name to a patient identification number will be stored separately in another locked 
file cabinet.  Clinical information will not be released without written permission of 
the subject, except as necessary for monitoring by the FDA.  The Investigator must 
also comply with all applicable privacy regulations (e.g., Health Insurance 
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
15.1 Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor.  Protocol 
amendments cannot be implemented without prior written IRB/IEC approval except 
as necessary to eliminate immediate safety hazards to patients.  A protocol 
amendment intended to eliminate an apparent immediate hazard to patients may 
be implemented immediately, provided the IRBs are notified within five working 
days. 
15.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of 
each participating center prior to study initiation.  Serious adverse experiences 
regardless of causality will be reported to the IRB/IEC in accordance with the 
standard operating procedures and policies of the IRB/IEC, and the Investigator 
will keep the IRB/IEC informed as to the progress of the study.  The Investigator 
will obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as 
protocol, protocol amendments, Investigator’s Brochure, consent forms, 
information concerning patient recruitment, payment or compensation procedures, 
or other pertinent information) will be submitted to the IRB/IEC.  The IRB/IECs 
written unconditional approval of the study protocol and the informed consent form 
will be in the possession of the Investigator before the study is initiated.  The 
IRB/IECs unconditional approval statement will be transmitted by the Investigator 

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to the Sponsor or designee prior to the shipment of study supplies to the site.  This 
approval must refer to the study by exact protocol title and number and should 
identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated 
without prior written IRB/IEC approval except when necessary to eliminate 
immediate hazards to the patients or when the change(s) involves only logistical or 
administrative aspects of the study.  Such modifications will be submitted to the 
IRB/IEC and written verification that the modification was submitted and 
subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted 
for review; serious and/or unexpected adverse experiences occurring during the 
study in accordance with the standard operating procedures and policies of the 
IRB; new information that may affect adversely the safety of the patients of the 
conduct of the study; an annual update and/or request for re-approval; and when 
the study has been completed. 
15.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, 
ICH GCP, US Code of Federal Regulations for Protection of Human Subjects (21 
CFR 50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance 
Portability and Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA 
authorization and provide the documents to the Sponsor or designee for approval 
prior to submission to the IRB/IEC.  The consent form generated by the 
Investigator must be acceptable to the Sponsor and be approved by the IRB/IEC.  
The written consent document will embody the elements of informed consent as 
described in the International Conference on Harmonisation and will also comply 
with local regulations. The Investigator will send an IRB/IEC-approved copy of the 
Informed Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each subject 
prior to entering the subject into the trial.  Information should be given in both oral 
and written form and subjects (or their legal representatives) must be given ample 
opportunity to inquire about details of the study.  If appropriate and required by the 
local IRB/IEC, assent from the subject will also be obtained.  If a subject is unable 
to sign the informed consent form (ICF) and the HIPAA authorization, a legal 
representative may sign for the subject.   A copy of the signed consent form (and 
assent) will be given to the subject or legal representative of the subject and the 
original will be maintained with the subject’s records. 
15.4 Publications  
The preparation and submittal for publication of manuscripts containing the study 
results shall be in accordance with a process determined by mutual written 
agreement among the study Sponsor and participating institutions.  The publication 
or presentation of any study results shall comply with all applicable privacy laws, 

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including, but not limited to, the Health Insurance Portability and Accountability Act 
of 1996.  
15.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes 
after notifying the Sponsor (or designee), except when to protect the safety, 
rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB 
review and approval meet federal guidelines, as stated in § 21 CFR, parts 50 
and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the 
study, in accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct 
of the study are informed about their obligations in meeting the above 
commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 
and to make those records available for inspection with the Sponsor (or 
designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will 
be responsible for initial and continuing review and approval of the clinical 
study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the 
research activity and all unanticipated problems involving risks to subjects or 
others (to include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, 
except when necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical