Clinical trial NCT03004924
Conditions: Bacterial Conjunctivitis
Sponsor: Shire
Start date: 2017-03-29; Completion date: 2018-10-01
Enrollment: 753 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if an investigational treatment is effective compared with placebo and PVP-Iodine in the treatment of adults and children with bacterial conjunctivitis.

Detailed description:

Arms: arm 1: Participants will instill 1 drop of SHP640 (povidone-iodine \[PVP-I\] 0.6 percent \[%\] and Dexamethasone 0.1%) ophthalmic suspension in each eye 4 times daily (QID) for 7 days. arm 2: Participants will instill 1 drop of PVP-I 0.6% ophthalmic solution in each eye 4 times QID for 7 days arm 3: Participants will instill 1 drop of placebo ophthalmic solution in each eye 4 times QID for 7 days.
Interventions: intervention 1: SHP640 intervention 2: PVP-I 0.6% intervention 3: Placebo
Intervention descriptions: intervention 1: Instill 1 drop of SHP640 (povidone-iodine \[PVPI\] 0.6% and Dexamethasone 0.1%) ophthalmic suspension in each eye QID (with a minimum of 2 hours between doses) for 7 days. intervention 2: Instill 1 drop of PVP-I 0.6% ophthalmic solution in each eye 4 times QID (with a minimum of 2 hours between doses) for 7 days. intervention 3: Instill 1 drop of placebo ophthalmic solution in each eye 4 times QID (with a minimum of 2 hours between doses) for 7 days.

Protocol documents:
Prot_003.pdf: 
PROTOCOL SHP640-303
TITLE:
A Phase 3, Multi-center, Randomized, Double-Masked Study to 
Evaluate the Clinical Efficacy and Safety of SHP640 (PVP-Iodine 0.6% 
and Dexamethasone 0.1%) Ophthalmic Suspension Compared to 
Placebo in the Treatment of Bacterial Conjunctivitis
DRUG:
SHP640
IND:
75,723
EUDRACT NO:
2016-003361-25
SPONSOR:
Shire
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 27 September 2016
Amendment 1: 28 November 2016
Amendment 2: 15 February 2017
Amendment 3: 13 December 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire




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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to the Shire Global Pharmacovigilance and Risk Management 
Department. Applicable fax numbers and e-mail address can be found on the form (sent under 
separate cover). A copy of this form must also be sent to the contract research organization 
(CRO)/Shire medical monitor by fax or e-mail using the details below.
Fax: 
Email: 
For protocol- or safety-related issues in the United States (US) and North American region, 
the investigator must contact the Shire medical monitor:
, MBBS, DPM, MS
Primary telephone number:
Fax: 
Alternate number:
For protocol- or safety-related issues in regions other than North America, the investigator 
must contact the Quintiles 24/7 Emergency Contact center:
Primary telephone number: 
Alternate number:






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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA), 


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................6
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF ABBREVIATIONS........................................................................................................12
STUDY SYNOPSIS ......................................................................................................................13
1.
BACKGROUND INFORMATION.......................................................................................22
1.1
Indication and Current Treatment Options...............................................................22
1.2
Product Background and Clinical Information ........................................................22
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................23
2.1
Rationale for the Study.............................................................................................23
2.2
Study Objectives ......................................................................................................23
2.2.1
Primary Objective..................................................................................................23
2.2.2
Key Secondary Objective ......................................................................................23
2.2.3
Secondary Objectives.............................................................................................23
2.2.4
Exploratory Objectives ..........................................................................................24
3.
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ..................................................................................25
3.2
Duration and Study Completion Definition .............................................................25
3.3
Sites and Regions .....................................................................................................26
4.
STUDY POPULATION.........................................................................................................27
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................28
4.3
Reproductive Potential .............................................................................................29
4.3.1
Female Contraception............................................................................................29
4.4
Discontinuation of Subjects .....................................................................................30
4.4.1
Reasons for Discontinuation..................................................................................31
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................32
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................33
5.1
Prior Treatment ........................................................................................................33
5.2
Concomitant Treatment............................................................................................33
5.2.1
Permitted Treatment...............................................................................................33
5.2.2
Prohibited Treatment .............................................................................................33


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6.
INVESTIGATIONAL PRODUCT ........................................................................................35
6.1
Identity of Investigational Product...........................................................................35
6.1.1
Masking the Treatment Assignment ......................................................................35
6.1.2
Commercially Obtained Investigational Product...................................................35
6.2
Administration of Investigational Product(s)...........................................................35
6.2.1
Interactive Response Technology for Investigational Product Management ........35
6.2.2
Allocation of Subjects to Treatment ......................................................................35
6.2.3
Dosing....................................................................................................................36
6.2.4
Unmasking the Treatment Assignment..................................................................36
6.3
Labeling, Packaging, Storage, and Handling ...........................................................36
6.3.1
Labeling .................................................................................................................36
6.3.2
Packaging...............................................................................................................37
6.3.3
Storage ...................................................................................................................37
6.3.4
Special Handling....................................................................................................38
6.4
Drug Accountability.................................................................................................38
6.5
Subject Compliance..................................................................................................39
7.
STUDY PROCEDURES........................................................................................................40
7.1
Study Schedule.........................................................................................................40
7.1.1
Visit 1 (Day 1) .......................................................................................................40
7.1.2
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8) ............................................................42
7.1.3
Visit 5 (End of Study or Early Termination) .........................................................42
7.1.4
Additional Care of Subjects after the Study ..........................................................42
7.2
Study Evaluations and Procedures ...........................................................................42
7.2.1
Demographic and Other Baseline Characteristics .................................................42
7.2.2
Efficacy..................................................................................................................43
7.2.3
Safety .....................................................................................................................44
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................47
8.1
Definition of Adverse Events, Period of Observation, and Recording of 
Adverse Events.........................................................................................................47
8.1.1
Severity Categorization..........................................................................................47
8.1.2
Relationship Categorization...................................................................................48
8.1.3
Outcome Categorization ........................................................................................48
8.1.4
Symptoms of the Disease Under Study .................................................................48
8.1.5
Pregnancy...............................................................................................................49
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................49
8.2
Serious Adverse Event Procedures ..........................................................................50
8.2.1
Reference Safety Information................................................................................50
8.2.2
Reporting Procedures.............................................................................................50


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8.2.3
Serious Adverse Event Definition .........................................................................51
8.2.4
Serious Adverse Event Collection Time Frame.....................................................51
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................51
8.2.6
Fatal Outcome........................................................................................................52
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................52
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................53
9.1
Data Collection.........................................................................................................53
9.2
Clinical Data Management.......................................................................................53
9.3
Data Handling Considerations..................................................................................53
9.4
Statistical Analysis Process......................................................................................53
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......54
9.6
Sample Size Calculation and Power Considerations................................................54
9.7
Study Population ......................................................................................................55
9.8
Efficacy Analyses.....................................................................................................55
9.8.1
Study Eye Designation...........................................................................................55
9.8.2
Primary Efficacy Endpoint ....................................................................................56
9.8.3
Key Secondary Efficacy Endpoints .......................................................................57
9.8.4
Secondary Efficacy Endpoints...............................................................................57
9.8.5
Exploratory Efficacy Endpoints.............................................................................58
9.9
Safety Analyses........................................................................................................58
9.10
Other Analyses .........................................................................................................59
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................60
10.1
Sponsor’s Responsibilities .......................................................................................60
10.1.1 Good Clinical Practice Compliance.......................................................................60
10.1.2 Indemnity/Liability and Insurance.........................................................................60
10.1.3 Public Posting of Study Information......................................................................60
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................61
10.1.5 Study Suspension, Termination, and Completion..................................................61
10.2
Investigator’s Responsibilities .................................................................................61
10.2.1 Good Clinical Practice Compliance.......................................................................61
10.2.2 Protocol Adherence and Investigator Agreement..................................................62
10.2.3 Documentation and Retention of Records.............................................................62
10.3
Ethical Considerations..............................................................................................63
10.3.1 Informed Consent...................................................................................................63
10.3.2 Institutional Review Board or Ethics Committee..................................................64
10.4
Privacy and Confidentiality......................................................................................65


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10.5
Study Results/Publication Policy .............................................................................65
11. REFERENCES .......................................................................................................................67
12. APPENDICES ........................................................................................................................69
Appendix 1
Protocol History .....................................................................................70
Appendix 2
Scales and Assessments .........................................................................71


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LIST OF TABLES
Table 1
Schedule of Assessments .........................................................................................20
Table 2
Common Excluded Treatments and Associated Washout Periods ..........................34
LIST OF FIGURES
Figure 1 SHP640-303 Study Design.......................................................................................25


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LIST OF ABBREVIATIONS
AAP
American Academy of Pediatrics
AE
adverse event
BCVA
best corrected visual acuity
CFU
colony-forming unit
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
EC
ethics committee
eCRF
electronic case report form
EMA
European Medicines Agency
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
HSV
Herpes Simplex Virus
IA
interim analysis
ICH
International Conference on Harmonisation
IMP
investigational medicinal product
IOP
intraocular pressure
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
mITT
modified intent-to-treat
MRSA
methicillin-resistant Staphylococcus aureus
NCS
not clinically significant
NF
National Formulary
ODS
ocular discomfort scale
PVP-I
povidone-iodine
QID
4 times a day
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment-emergent adverse event
US
United States
USP
United States Pharmacopeia
VA
visual acuity
VBR
Validated Bulbar Redness


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STUDY SYNOPSIS
Protocol number: SHP640-303
Drug: SHP640
Title of the study: A Phase 3, Multi-center, Randomized, Double-Masked Study to Evaluate the Clinical Efficacy 
and Safety of SHP640 (PVP-Iodine 0.6% and Dexamethasone 0.1%) Ophthalmic Suspension Compared to Placebo 
in the Treatment of Bacterial Conjunctivitis
Number of subjects (total and for each treatment arm):
Total subjects: Approximately 721
SHP640 treatment arm: Approximately 309
Povidone-iodine (PVP-I) treatment arm: Approximately 103
Placebo treatment arm: Approximately 309 
Investigator(s): multicenter study
Site(s) and Region(s): 
The study will be conducted in approximately 90 sites across North America, South America, Asia/Pacific, Europe, 
the Middle East and Africa.
Study period (planned):
December 2016 to March 2018
Clinical phase:
3
Objectives:
Primary:
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical resolution (defined as 
absence of bulbar conjunctival injection and ocular conjunctival discharge) compared with placebo in the treatment 
of subjects with bacterial conjunctivitis in the study eye at Visit 3 (Day 5). 
Secondary:
The key secondary objective of this study is to evaluate the efficacy of SHP640 based on bacterial eradication 
(defined as absence of all bacterial species present at or above pathological threshold at baseline) compared with 
placebo in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 (Day 5).
Secondary objectives of this study are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints:

Clinical resolution of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12)

Bacterial eradication at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12)

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival injection and ocular 
conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

The global clinical score (sum of bulbar conjunctival injection and ocular conjunctival discharge) and change 
from baseline in the global clinical score at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12)

Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither injection nor 
discharge having a score of 2 at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the treatment of subjects 
with bacterial conjunctivitis

Use of rescue medication


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Rationale:
The clinical presentation of conjunctivitis is often nonspecific, and differential diagnosis of different types of 
conjunctivitis can be challenging (Azari and Barney 2013; O’Brien et al. 2009). Diagnostic testing to differentiate 
the underlying cause of infection is rarely performed in a clinical setting; misdiagnosis can occur in up to 50% of 
cases, which often results in improper antibiotic treatment (Visscher et al. 2009). Incorrect treatment can not only 
increase healthcare costs from unnecessary antibiotic prescriptions and repeat office visits but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or methicillin-resistant Staphylococcus 
aureus). In addition, there is also a risk of overuse and misuse of antibiotics, which are ineffective in the treatment 
of viral infections (Statham et al. 2008). An unmet medical need therefore exists for a safe and efficacious treatment 
that addresses both bacterial and adenoviral conjunctivitis, 2 of the leading causes of acute infectious conjunctivitis. 
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, with 
dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious and inflammatory 
components of adenoviral and bacterial conjunctivitis.
Investigational product, dose, and mode of administration:
The drug product is SHP640 (0.1% dexamethasone and 0.6% PVP-I) ophthalmic suspension.
The comparators are placebo ophthalmic solution and 0.6% PVP-I ophthalmic solution.
Subjects will instill 1 drop of investigational product in each eye 4 times daily (with a minimum of 2 hours between 
doses) for 7 days.
Methodology:
Once screening and baseline assessments are complete and subjects are confirmed eligible to enroll in the study, 
subjects will be randomized, and investigational product will be administered on the same day (Day 1). The first 
dose will be administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a 
day for 7 days. Additional visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). The study 
will last up to 13 days. 
Inclusion and exclusion criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions (by 
the parent(s), guardian, or legally authorized representative, if applicable).
2.
Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), guardian, or 
legally authorized representative(s) informed consent (and assent, if applicable) to participate in the 
study.
3.
Subjects of any age at Visit 1 (Note: subjects <3 months of age at Visit 1 must have been full-term, ie 
≥37 weeks gestational age at birth).
4.
Have a negative AdenoPlus® test in both eyes within 24 hours of Visit 1 or at Visit 1.
5.
Have a clinical diagnosis of suspected bacterial conjunctivitis in at least 1 eye confirmed by the 
presence of the following minimal clinical signs and symptoms in that same eye:
5.1. Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤4 days prior to Visit 1
5.2. Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection Scale
5.3. Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
6.
Be willing to discontinue contact lens wear for the duration of the study.


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7.
Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as measured using 
an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will be assessed by an age 
appropriate method in accordance with the AAP Policy Statement for Visual System Assessment in 
Infants, Children, and Young Adults by Pediatricians (Donahue and Baker 2016; American Academy 
of Pediatrics 2016). The policy statement recommends formal vision screening can begin at 3 years of 
age. VA measurements for children under the age of 3 will be done at the discretion of the investigator. 
If not done, child should be able to fixate on and follow a moving object, except subjects <2 months of 
age who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion of 
the investigator.  
8.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of non-childbearing potential.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1.
Current or recurrent disease that could affect the action, absorption, or disposition of the 
investigational product, or clinical or laboratory assessments, per investigator’s discretion.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may make the 
subject unlikely to fully complete the study, or any condition that presents undue risk from the 
investigational product or procedures.
3.
Have known or suspected intolerance or hypersensitivity to the investigational product, closely related 
compounds, or any of the stated ingredients. 
4.
Prior enrollment in a FST-100 or SHP640 clinical study.
5.
Subjects who are employees, or immediate family members of employees (who are directly related to 
study conduct), at the investigational site.
6.
Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned for the 
period of the study.
7.
Have a preplanned overnight hospitalization during the period of the study.
8.
Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, iritis, 
ulcerative keratitis, chronic blepharoconjunctivitis), other than bacterial conjunctivitis.
9.
Have active or a history of ocular herpes.
10. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with the 
diagnosis of non-infectious conjunctivitis (except presumed seasonal/perennial allergic conjunctivitis), 
or non-bacterial ocular infection (eg, viral, fungal, acanthamoebal, or other parasitic). Note: history or 
concomitant presence of presumed seasonal or perennial allergic conjunctivitis signs/symptoms is not 
exclusionary.
11. Neonates or infants (ie, subjects less than 12 months of age) who have suspected or confirmed (based 
on the result of any test conducted prior to screening) conjunctivitis of gonococcal, chlamydial, 
herpetic or chemical origin.
12. Neonates or infants (ie, subjects less than 12 months of age) whose birth mothers had any sexually 
transmitted disease within 1 month of delivery or any history of genital herpes.
13. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
14. Presence of any significant ophthalmic condition (eg, Retinopathy of Prematurity, congenital cataract, 
congenital glaucoma) or other congenital disorder with ophthalmic involvement that could affect study 
variables.
15. Be a known intraocular pressure (IOP) steroid responder, have a known history or current diagnosis of 
glaucoma, or be a glaucoma suspect.


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16. Have any known clinically significant optic nerve defects. 
17. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to previous corneal 
trauma or dry eye syndrome; presence of corneal epithelial defect or any significant corneal opacity at 
Visit 1.
18. Presence of significant, active condition in the posterior segment that requires invasive treatment (eg, 
intravitreal treatment with vascular endothelial growth factor inhibitors or corticosteroids) and may 
progress during the study participation period. 
19. Have used any topical ocular or systemic antibiotics within ≤7 days of enrollment. 
20. Have used any topical ocular non-steroidal anti-inflammatory drugs within ≤1 day of enrollment.
21. Have used any topical ophthalmic steroids in the last ≤14 days.
22. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 days 
prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no anticipated change in 
dose for the duration of the study. Topical dermal steroids are allowed except in the periocular area.
23. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
24. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all topical 
ophthalmic products for the duration of the study. Use of hot or cold compresses is also not permitted 
during the study.  
25. Have any significant ocular disease (eg, Sjogren’s syndrome) or any uncontrolled systemic disease or 
debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted diseases/infections, 
diabetes, or cystic fibrosis) that may affect the study parameters, per investigator’s discretion.
26. Any known history of immunodeficiency disorder or known active conditions predisposing to 
immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of active 
hepatitis A (anti-hepatitis A virus immunoglobulin M), or organ or bone marrow transplantation.
27. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study.
Maximum duration of subject involvement in the study:
Subject participation will last up to 13 days.
Screening, randomization, and the first treatment administration will occur at Visit 1 (Day 1). 
Additional visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). 
All follow-up procedures will be conducted at Visit 5 (Day 12).
Endpoints and statistical analysis:
Primary Efficacy Endpoint:
Clinical resolution status (defined as absence of bulbar conjunctival injection and ocular conjunctival discharge) in 
the study eye at Visit 3 (Day 5) between SHP640 and placebo.
Key Secondary Efficacy Endpoints:
Bacterial eradication status (defined as absence of all bacterial species present at or above pathological threshold at 
baseline) in the study eye at Visit 3 (Day 5) between SHP640 and placebo.


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Secondary Efficacy Endpoints:

Clinical resolution status of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) in the study 
eye

Bacterial eradication status (defined as absence of all bacterial species present at or above pathological 
threshold at baseline) as assessed by bacterial culture at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) in the study 
eye 

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival injection and ocular 
conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye 

The global clinical score (defined as the sum of bulbar conjunctival injection and ocular conjunctival discharge) 
and change from baseline in the global clinical score at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in 
the study eye 

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12) in the study eye 

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with neither injection nor 
discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye 

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in 
the study eye 

Use of rescue medication 
Safety Endpoints:

BCVA

Slit lamp biomicroscopy 

Non-dilated/dilated fundus examination

Urine pregnancy testing (for females of childbearing potential)

Adverse events (AEs)
Statistical Methods:
The analyses on primary, key secondary, secondary, and exploratory efficacy endpoints will be performed on the 
modified intent-to-treat (mITT) population (unless specified otherwise) and will be presented by treatment group. 
Additional sensitivity analyses may be conducted on the intent-to-treat (ITT) population. Safety analyses will be 
conducted on the safety population.
For both efficacy and safety analyses, baseline is defined as the assessments taken prior to treatment at Visit 1 
(Day 1).
Analysis Populations:
The safety population will include all subjects who receive at least 1 dose of investigational product.
The ITT population will include all randomized subjects. 
The mITT population consists of a subset of the ITT population who receive at least 1 dose of investigational 
product and have a positive bacterial culture (presence of 1 or more bacterial species at or above pathological 
threshold) at baseline in the study eye.


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Designation of Study Eye:
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a score of at least 1 for 
both ocular  conjunctival discharge and bulbar conjunctival redness at baseline (baseline is defined as the 
assessments taken prior to treatment at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive bacterial culture (presence of 1 or more bacterial 
species at or above pathological threshold) at baseline or both eyes eligible and both with a non-positive 
bacterial culture (absence of any bacterial species at or above pathological threshold) at baseline, the study eye 
will be the eye with the highest global clinical score (sum of bulbar conjunctival injection and ocular 
conjunctival discharge) at baseline. If both eyes have the same global clinical score at baseline, then the study 
eye will be the right eye.

For subjects with both eyes eligible with a positive bacterial culture in one eye at baseline, the baseline bacterial 
culture positive eye will be the study eye.

For subjects with only 1 eligible eye, the eligible eye will be the study eye irrespective of its baseline bacterial 
culture status.
Primary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. There is a single primary 
comparison for the single primary endpoint. Therefore, no adjustment of multiplicity is needed for the hypothesis 
testing for the primary objective.
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 5) will be compared between the 
SHP640 and placebo group. The comparison will be based on the proportion of subjects with clinical resolution in 
the study eye at Visit 3 (Day 5) using Fisher’s Exact test at 2-sided 0.0499 significance level.
If subjects have missing clinical resolution status at Visit 3 (Day 5), then the last post-baseline observation will be 
carried forward for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with clinical resolution in the 
study eye between SHP640 ophthalmic Solution and placebo with the alternative of the non-zero difference in the 
proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 2-sided Fisher’s Exact test at 4.99% level 
of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical method(s) including 
methods of imputation of missing data. Sensitivity analyses may be conducted in the ITT in addition to the mITT.
Key Secondary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. The key secondary efficacy 
endpoint of this study is bacterial eradication status in the study eye at Visit 3 (Day 5) between SHP640 and placebo. 
In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary hypotheses will be tested 
sequentially. Each hypothesis will be tested using Fisher’s Exact test at 2-sided 4.99% level with null hypothesis of 
no difference in the proportion of subjects for the endpoint between the 2 treatment groups. 
First, the primary efficacy endpoint will be tested. Only if the null hypothesis for the primary efficacy endpoint is 
rejected at 4.99% level, then the key secondary efficacy endpoint of bacterial eradication will be tested to compare 
the proportion of subjects with bacterial eradication between the SHP640 and placebo treatment group. If subjects 
have missing bacterial eradication at Visit 3 (Day 5), then the last post-baseline observation will be carried forward 
for the determination of bacterial eradication of the study eye. 
Sensitivity analyses will also be done on the key secondary efficacy endpoint using similar methods as described 
above.


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Secondary Efficacy Analyses:
No hypothesis testing is planned for the secondary efficacy endpoints. All secondary efficacy endpoints will be 
summarized by treatment groups using descriptive statistics at each assessment visit. Continuous endpoints will be 
summarized by number of subjects (n), mean, median, standard deviation, minimum, maximum, and confidence 
intervals (CIs). Binary endpoints will be summarized by number of subjects (n), frequencies, proportions, and CIs. 
Time to event endpoint will be summarized by Kaplan-Meier survival estimates.
Safety Analyses:
Safety data will be presented for the safety population by treatment group and overall.
Safety data collected at baseline prior to treatment (Visit 1/Day 1) will be used as the baseline value for safety 
analysis. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The number of subjects and 
percentage with a treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated 
overall, by system organ class, by preferred term, and by treatment group and overall. TEAEs will be further 
summarized by severity and relationship to investigational product. AEs related to investigational product, AEs 
leading to withdrawal, serious AEs, and deaths will be similarly summarized and listed. Any AE that occurs after the 
first dose of investigational product instillation will be considered a TEAE.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or a non-ocular AE.
Slit lamp biomicroscopy, non-dilated/dilated fundus exam, BCVA, and urine pregnancy test (for females of 
childbearing potential) will be descriptively summarized by treatment group and overall at each applicable visit.


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Study Schedule
Table 1
Schedule of Assessments
Procedure
(All ocular assessments and 
procedures performed bilaterally)
Visit 1
Screeninga and 
Baseline
(Day 1)
-1 Day
Visit 2
(Day 3)
+1 Day
Visit 3
(Day 5)
Visit 4
(Day 8)
+1 Day
Visit 5b
(Day 12)
+2 Days
Informed consent/assenta
X
Inclusion/exclusion criteriaa
X
Medical history 
X
Demographics
X
Concomitant medications
X
X
X
X
X
Urine pregnancy test
Xc
Xc
Ocular discomfort scale
X
X
X
X
X
Best corrected visual acuity
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
Bulbar conjunctival injection 
evaluation
X
X
X
X
X
Ocular conjunctival discharge 
evaluation
X
X
X
X
X
AdenoPlus® test
Xd
Conjunctival swab for bacterial 
culturee
X
Xf
Xf
Xf
X
Conjunctival swab to test for HSV, 
and chlamydia and gonorrheal
X
Non-dilated/dilated fundus 
examinationk
X
X
Randomizationg
X
Dispense investigational producth
X
Instill investigational product
Xh
Xi
Xi
Collect investigational product
X
Xb
Compliance assessment
X
X
X
Xb
Drug accountability
X
Xb


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Table 1
Schedule of Assessments
Procedure
(All ocular assessments and 
procedures performed bilaterally)
Visit 1
Screeninga and 
Baseline
(Day 1)
-1 Day
Visit 2
(Day 3)
+1 Day
Visit 3
(Day 5)
Visit 4
(Day 8)
+1 Day
Visit 5b
(Day 12)
+2 Days
Adverse events
Xj
X
X
X
X
Study completion
X
ET=early termination; 
a Informed consent and confirmation of inclusion/exclusion criteria can be conducted on Day -1; these criteria must 
be reconfirmed on Day 1.
b If investigational product is discontinued, regardless of the reason, all discontinued subjects should proceed to 
Visit 5 whenever possible. Subjects who discontinue the study and proceed to Visit 5 should perform all Visit 5 
assessments as well as drug return, compliance, and accountability.
c Women of childbearing potential, prior to enrollment and at exit from the study
d If not previously conducted within 24 hours of Visit 1 (Day 1)
e One swab sample from inferior conjunctival cul-de-sac of each eye will be collected for all bacterial testing.
f Conjunctival swab samples MUST be taken at least 12 hours after the last dose of investigational product at 
Visits 2, 3, 4, and ET, if applicable.
g All assessments, randomization, and investigational product instillation on Day 1 must take place with sufficient 
time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses).
h The investigational product bottle should be shaken well prior to use at each dosing. The first dose will be 
administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a day for 
7 days.
i Investigational product instillation should only be performed in-office if it is necessary.
j Monitoring for adverse events will begin after informed consent is obtained.
k If a non-dilated fundus exam is not feasible, a dilated examination should be conducted. For each subject, the exam 
should be conducted the same way (either non-dilated or dilated) at both Visits 1 and 5 (or ET).  
l This sample will be used for baseline HSV testing for all subjects. For subjects <2 months of age, testing for 
chlamydia and gonorrhea detection will also be conducted using the same sample.


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Conjunctivitis affects all populations worldwide of all ages and social strata, irrespective of 
gender. Infectious conjunctivitis (adenoviral and bacterial) represents a serious public health 
issue due to a risk of highly infectious epidemics, lost productivity, significant subject 
discomfort, and, in some cases, permanent visual compromise from long-term, immune-mediated 
sequelae (Capriotti et al., 2010; Ford et al., 1987; Gordon et al., 1993; Nauheim et al., 1990; 
Pelletier et al., 2009). Bacterial conjunctivitis is the second-most common cause of infectious 
conjunctivitis with a viral etiology being the most common cause (Azari and Barney, 2013). 
Bacterial etiology is more common in children, potentially accounting for 50-75% of all 
infectious conjunctivitis cases occurring in children (Azari and Barney, 2013). The condition is 
caused by a wide variety of bacteria, including gram-positive species such as Staphylococcus 
aureus and Streptococcus pneumoniae and gram-negative species such as Haemophilus 
influenzae, Chlamydia trachomatis, and Moraxella catarrhalis (Azari and Barney, 2013; Chen 
and Starr, 2008; CDC, 2010; Dias et al., 2013; Haas et al., 2005; Patel et al., 2007; Rours et al., 
2008). Bacterial conjunctivitis typically lasts for 7 to 10 days, yet, in the absence of adequate 
treatment, it can last for weeks or months.
1.2
Product Background and Clinical Information
SHP640, a novel topical ophthalmic suspension, is currently under development for the treatment 
of infectious conjunctivitis (adenoviral and bacterial).
SHP640 contains 2 active ingredients: povidone-iodine (PVP-I) and dexamethasone. PVP-I is a 
multivalent broad-spectrum local antiseptic with bactericidal and fungicidal properties. The 
effect on vegetative cells of various bacteria and fungi is due to the liberation of free iodine from 
the complex. It is effective against many viruses, protozoa, yeasts, cysts, and spores (Betadine, 
2004). Dexamethasone is a corticosteroid routinely used as a topical ophthalmic suspension for 
the treatment of ocular inflammation. It suppresses the inflammatory response to a variety of 
causes of inflammation (Maxidex, 2007). Both components are currently approved for use in 
other indications (at similar or higher concentrations) and have been shown to be safe and 
efficacious for use on the ocular surface in humans. The combination of PVP-I and 
dexamethasone has been shown to rapidly kill common ocular pathogens, including viruses, 
gram-positive bacteria (including methicillin-resistant Staphylococcus aureus [MRSA]), and 
gram-negative bacteria (Pelletier et al., 2013).
Always refer to the latest version of the SHP640 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy, and safety of SHP640. 


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The clinical presentation of conjunctivitis is often nonspecific, and differential diagnosis of 
different types of conjunctivitis can be challenging (Azari and Barney, 2013; O'Brien et al., 
2009). Diagnostic testing to differentiate the underlying cause of infection is rarely performed in 
a clinical setting; misdiagnosis can occur in up to 50% of cases, which often results in improper 
antibiotic treatment (Visscher et al., 2009). Incorrect treatment can not only increase healthcare 
costs from unnecessary antibiotic prescriptions and repeat office visits, but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or MRSA). In 
addition, there is also a risk of overuse and misuse of antibiotics, which are ineffective in the 
treatment of viral infections (Statham et al., 2008). An unmet medical need therefore exists for a 
safe and efficacious treatment that addresses both bacterial and adenoviral conjunctivitis, 2 of the 
leading causes of acute infectious conjunctivitis.
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, 
with dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious 
and inflammatory components of adenoviral and bacterial conjunctivitis.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical 
resolution (defined as absence of bulbar conjunctival injection and ocular conjunctival discharge) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye 
at Visit 3 (Day 5). 
2.2.2
Key Secondary Objective
The key secondary objective is to evaluate the efficacy of SHP640 based on bacterial eradication 
(defined as absence of all bacterial species present at or above pathological threshold at baseline) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye 
at Visit 3 (Day 5).
2.2.3
Secondary Objectives
The secondary objectives are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints: 

Clinical resolution of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12)

Bacterial eradication at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) 

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12)


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
The global clinical score (sum of bulbar conjunctival injection and ocular conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 
3 (Day 5), 4 (Day 8), and 5 (Day 12) 

Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) 

Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither 
injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12) 

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 
4 (Day 8), and 5 (Day 12) 

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the 
treatment of subjects with bacterial conjunctivitis

Use of rescue medication
2.2.4
Exploratory Objectives
The exploratory objectives of this study are as follows: 

To evaluate ocular discomfort due to conjunctivitis symptoms in subjects receiving SHP640 
compared to PVP-I and placebo at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)


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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
SHP640-303 is a global, multicenter, randomized, double-masked, parallel-group, 
placebo-controlled study designed to demonstrate the safety and efficacy of SHP640 ophthalmic 
suspension compared to placebo in treating bacterial conjunctivitis. In addition, an exploratory 
arm of PVP-I 0.6% ophthalmic solution will be included.
Approximately 721 subjects will be randomized into the study at Visit 1 (Day 1). Randomization 
will be stratified by age to maintain the randomization ratio among subjects <6 years, 6 to 
<18 years, and subjects ≥18 years. Subjects will be randomized 3:1:3 to receive either SHP640, 
PVP-I, or placebo within each stratum. 
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced randomization will be used in this study to 
maintain the randomization ratio within each stratum. 
Once screening and baseline assessments are complete and subjects are confirmed eligible to 
enroll in the study, subjects will be randomized, and investigational product will be administered 
on the same day (Day 1). The first dose will be administered by site staff on Day 1, and 
thereafter subjects will administer 1 drop in each eye 4 times a day (QID) for 7 days. Additional 
visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). All follow-up 
procedures will be conducted at Visit 5 (Day 12). The study will last up to 13 days. 
Figure 1 provides the study design.
Figure 1
SHP640-303 Study Design
PVP-I=povidone iodine
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 13 days. The 
study will be completed in approximately 1.5 years. 


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The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit (Visit 5) 
or contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
The study will be conducted in approximately 90 sites across North America, South America, 
Asia/Pacific, Europe, Middle East, and Africa.


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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed. If a subject is younger 
than the legal age of consent (per local laws), the subject’s parent(s), guardian, or legally 
authorized representative will provide written informed consent; the subject will provide verbal 
or written assent as appropriate.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions (by the parent(s), guardian, or legally authorized representative, if applicable).
2. Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), 
guardian, or legally authorized representative(s) informed consent (and assent, if applicable) 
to participate in the study.
3. Subjects of any age at Visit 1 (Note: subjects <3 months of age at Visit 1 must have been 
full-term, ie, ≥37 weeks gestational age at birth).
4. Have a negative AdenoPlus® test in both eyes within 24 hours of Visit 1 or at Visit 1.
5. Have a clinical diagnosis of suspected bacterial conjunctivitis in at least 1 eye confirmed by 
the presence of the following minimal clinical signs and symptoms in that same eye:

Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤4 days prior to 
Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection 
Scale

Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
6. Be willing to discontinue contact lens wear for the duration of the study.
7. Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as 
measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will 
be assessed by an age appropriate method in accordance with the AAP Policy Statement for 
Visual System Assessment in Infants, Children, and Young Adults by Pediatricians 
(Donahue and Baker, 2016; American Academy of Pediatrics, 2016). The policy statement 
recommends formal vision screening can begin at 3 years of age. VA measurements for 
children under the age of 3 will be done at the discretion of the investigator. If not done, child 
should be able to fixate on and follow a moving object, except subjects <2 months of age 
who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion 
of investigator.
8. Male, or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential.


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4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. Current or recurrent disease that could affect the action, absorption, or disposition of the 
investigational product, or clinical or laboratory assessments, per investigator’s discretion.
2. Current or relevant history of physical or psychiatric illness, any medical disorder that may
make the subject unlikely to fully complete the study, or any condition that presents undue 
risk from the investigational product or procedures.
3. Have known or suspected intolerance or hypersensitivity to the investigational product, 
closely related compounds, or any of the stated ingredients. 
4. Prior enrollment in a FST-100 or SHP640 clinical study.
5. Subjects who are employees, or immediate family members of employees (who are directly 
related to study conduct), at the investigational site.
6. Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned 
for the period of the study.
7. Have a preplanned overnight hospitalization during the period of the study.
8. Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, 
iritis, ulcerative keratitis, chronic blepharoconjunctivitis), other than bacterial conjunctivitis.
9. Have active or a history of ocular herpes.
10. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with 
the diagnosis of non-infectious conjunctivitis (except presumed seasonal/perennial allergic 
conjunctivitis) or non-bacterial ocular infection (eg, viral, fungal, acanthamoebal, or other 
parasitic). Note: history or concomitant presence of presumed seasonal or perennial allergic 
conjunctivitis signs/symptoms is not exclusionary.
11. Neonates or infants (ie, subjects less than 12 months of age) who have suspected or 
confirmed (based on the result of any test conducted prior to screening) conjunctivitis of 
gonococcal, chlamydial, herpetic or chemical origin.
12. Neonates or infants (ie, subjects less than 12 months of age) whose birth mothers had any 
sexually transmitted disease within 1 month of delivery or any history of genital herpes.
13. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
14. Presence of any significant ophthalmic condition (eg, Retinopathy of Prematurity, congenital 
cataract, congenital glaucoma) or other congenital disorder with ophthalmic involvement that 
could affect study variables.
15. Be a known intraocular pressure (IOP) steroid responder, have a known history or current 
diagnosis of glaucoma or be a glaucoma suspect.
16. Have any known clinically significant optic nerve defects. 


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17. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to 
previous corneal trauma or dry eye syndrome; presence of corneal epithelial defect or any 
significant corneal opacity at Visit 1.
18. Presence of significant, active condition in the posterior segment that requires invasive 
treatment (eg, intravitreal treatment with vascular endothelial growth factor inhibitors or 
corticosteroids) and may progress during the study participation period. 
19. Have used any topical ocular or systemic antibiotics within ≤7 days of enrollment. 
20. Have used any topical ocular non-steroidal anti-inflammatory drugs within ≤1 day of 
enrollment.
21. Have used any topical ophthalmic steroids in the last ≤14 days.
22. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated 
≥30 days prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no 
anticipated change in dose for the duration of the study. Topical dermal steroids are allowed 
except in the periocular area.
23. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
24. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all 
topical ophthalmic products for the duration of the study. Use of hot or cold compresses is 
also not permitted during the study.  
25. Have any significant ocular disease (eg, Sjogren’s syndrome) or any uncontrolled systemic 
disease or debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted 
diseases/infections, diabetes, or cystic fibrosis) that may affect the study parameters, per 
investigator’s discretion.
26. Any known history of immunodeficiency disorder or known active conditions predisposing 
to immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of  
active hepatitis A (anti-hepatitis A virus immunoglobulin M), or organ or bone marrow 
transplantation.
27. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study.
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception throughout the study period. If hormonal contraceptives are used, they should be 
administered according to the package insert. Females of childbearing potential who are not 
currently sexually active must agree to use acceptable contraception, as defined below, if they 
become sexually active during the period of the study.


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Female children and adolescent subjects should be either:

Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine pregnancy test at Visit 1. Females of 
childbearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Adult female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and ≥age 51 years)

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of childbearing potential with a negative urine pregnancy test at Visit 1 and prior to 
randomization. Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use acceptable methods of contraception. 
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Intrauterine hormone-releasing systems plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam) 

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the screening visit (Visit 1), plus condoms. 
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). 
Rescue treatment with a licensed antibiotic according to the local standard of care should be 
provided to subjects if, in the judgment of the investigator, there is no clinical improvement or 
worsening of their condition to an extent that it would be in the best interest of the subject to be 
treated with an alternate therapy for safety reasons. In such instances, the investigational product 
should be discontinued, Visit 5 evaluations be performed at the time of subject discontinuation 
after which rescue treatment will be started. 
The investigator is encouraged to discuss withdrawal of a subject from investigational product 
with the medical monitor if necessary.


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If investigational product is discontinued for any reason other than a positive HSV baseline test, 
the evaluations listed for Visit 5 are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified follow-up (proceed 
to Visit 5). Comments (spontaneous or elicited) or complaints made by the subject must be 
recorded in the source documents. The reason for termination and the date of stopping 
investigational product must be recorded in the case report form (CRF) and source documents.
Subjects who test positive for ocular HSV at baseline in either eye should have their 
investigational product discontinued, and should receive alternate appropriate treatment as 
needed based on the investigator’s judgment. These subjects should be followed for the 
remaining duration of study at regularly scheduled visits, and all safety related assessments 
should be completed (AEs, BCVA, slit lamp biomicroscopy at all visits [fundus exam at Visit 5], 
concomitant medications at all visits, and pregnancy test [if the subject is a female of 
childbearing potential]).
If a subject <2 months of age has a positive CT-NG test for any one of the two Visit 1 samples, 
the subject will be discontinued from the study and started with alternate standard of care therapy 
per the investigator’s clinical judgment.
Subject numbers for subjects who discontinue will not be reused.
4.4.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF. 
Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol deviation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Physician decision

Study terminated by sponsor

Withdrawal by parent(s)/guardian/legally authorized representative (if applicable)

Other (If “Other” is selected, the investigator must specify on the CRF.)


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4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.


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5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment received within 30 days prior to the screening visit (Visit 1; or 
pharmacokinetic equivalent of 5 half-lives, whichever is longer) and through the final study 
contact (including protocol-defined follow-up period) must be recorded on the appropriate CRF 
page.
5.1
Prior Treatment
Prior treatment includes all treatment received within 30 days prior to the screening visit 
(Visit 1) (or pharmacokinetic equivalent of 5 half-lives, whichever is longer). Prior treatment 
information must be recorded on the appropriate CRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment other than the investigational production taken 
between the dates of the first dose of investigational product and the end of Visit 5 (the end of 
study visit), inclusive. Concomitant treatment information must be recorded on the appropriate 
CRF page.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
Medications not indicated as prohibited are permitted, including treatments for general 
non-excluded medical conditions.
In the event of an emergency, any needed medications may be prescribed without prior approval, 
but the medical monitor must be notified of the use of any prohibited medications immediately 
thereafter.
5.2.2
Prohibited Treatment
Table 2 details the washout period for common prior treatments that are excluded medications 
for this study. 


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Table 2
Common Excluded Treatments and Associated Washout Periods
Minimum Time Prior to First Dose
Notes
Treatment
30 days 
14 days
7 days
1 day
2 hours
Topical ocular NSAIDs
X
Topical ocular or systemic antibiotics
X
Topical ophthalmic steroids
X
Systemic corticosteroid agents
X
Stable use of inhaled or nasal 
corticosteroids
X
Allowed ≥30 days if 
no anticipated dose 
changes during the 
study
Noncorticosteroid immunosuppressive 
agents
X
Topical ophthalmic solutions, 
including tear substitutes, and OTC 
preparations (ie, lid scrubs)
X
Must be able to 
discontinue use for 
the duration of the 
study
NSAID=non-steroidal anti-inflammatory drug; OTC=over-the-counter
Treatments not listed in Table 2 are considered permitted. 


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
Three test products will be used in the clinical development program. The drug product is 
SHP640 (0.1% dexamethasone and 0.6% PVP-I) ophthalmic suspension, the comparator is 0.6% 
PVP-I ophthalmic solution, and the placebo product is placebo ophthalmic solution. Each of 
these test products are manufactured aseptically and filled in sterile plastic ophthalmic bottles. 
The placebo contains 2 additional ingredients relative to the others: benzalkonium chloride, 
United States Pharmacopeia (USP), EP, used as a preservative, and caramel color, National 
Formulary (NF), included to match the dark brown color of the PVP-I active ingredient. 
Additional information on the 3 test products is provided in the current SHP640 investigator’s 
brochure.
6.1.1
Masking the Treatment Assignment
The packaging, appearance, and labeling of the test products will match. Colorant will be added 
to the placebo to match the appearance of SHP640 and the PVP-I ophthalmic solution. Treatment 
assignment will be determined by the randomization schedule.
6.1.2
Commercially Obtained Investigational Product
Not Applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive response technology (IRT) vendor will be used for this study to manage packaged 
investigational medicinal product (IMP) supply, IMP shipments, receipt of IMP at clinical sites, 
randomization of IMP to subjects, expiry tracking, IMP returns, accountability of IMP, and 
emergency unmasking. 
6.2.2
Allocation of Subjects to Treatment 
This is a double-masked, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment is 
automatically assigned by the IRT.
Randomization will be stratified by age to maintain the randomization ratio among subjects 
<6 years, 6 to <18 years, and subjects ≥18 years. 


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Subjects will be randomly assigned to receive SHP640, PVP-I 0.6%, or placebo based on a 3:1:3 
ratio (SHP640:PVP-I:placebo) within the randomization strata.
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced randomization (Pocock and Simon, 1975) will 
be used in this study to maintain the randomization ratio within each stratum. The randomization 
will be done centrally. 
6.2.3
Dosing
Subjects will be instructed to instill 1 drop of investigational product in each eye QID (with a 
minimum of 2 hours between doses) for 7 days.
Prior to administration of the first dose, the bottle should be removed from refrigeration and 
allowed to come to room temperature. The bottle will not be refrigerated before subsequent 
administrations. Storage requirements are discussed in Section 6.3.3.
The investigational product bottle should be shaken well prior to use at each dosing.
In-office dosing will only be performed at the first visit, and additionally if necessary. 
6.2.4
Unmasking the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor as soon as possible after the 
unmasking occurs. 
In the event that the treatment assignment is broken, the date and person who broke the code will 
be recorded by the IRT, and the reason for breaking will be recorded on the CRF. Upon breaking 
the mask, the subject will be withdrawn from the study but should complete Visit 5 (the end of 
study visit) to be followed up for safety purposes. Any code breaks that occur must be reported 
to the sponsor’s medical monitor. 
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and carton identification are applied to the investigational 
product(s) container. 
All investigational product is labeled with a minimum of the following: protocol number, 
investigational product identification number, dosage form, directions for use, storage 
conditions, expiry date (if applicable), batch number and/or packaging reference number, the 
statements “For clinical trial use only” and/or “CAUTION: New Drug – Limited by Federal (or 
US) Law to Investigational Use,” and the sponsor’s name and address. 


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Any additional labeling requirements for participating countries and/or controlled substances will 
also be included on the label, if necessary.
Space is allocated on the label so that the site representative can record the date dispensed, the 
subject’s initials (as permitted based on local laws), and the unique subject number.
Additional labels may, on a case-by-case basis, be applied to the investigational product in order 
to satisfy local or institutional requirements but must not: 

Contradict the clinical study label. 

Obscure the clinical study label. 

Identify the study subject by name. 
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers.
The investigational product bottle will be labeled and then placed into a 1x-labeled carton. This 
carton will then be secured with a tamper seal.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigational product must be stored at the site in a secure, refrigerated area (2-8ºC) 
accessible only to the investigator and his/her designees. The investigational product will be 
administered only to subjects enrolled in the clinical study, in accordance with the conditions 
specified in this protocol.
Undispensed investigational product should be stored under refrigeration at 2-8ºC.
Dispensed investigational product should be stored at room temperature below 30ºC. 
Investigational product should be protected from freezing and exposure to strong light.
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier and initials as permitted based on local laws 
on the investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. 


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The investigator is responsible for ensuring that the temperature is monitored throughout the 
duration of the study and that records are maintained; the temperature should be monitored 
continuously by using either an in-house system or a mechanical recording device such as a 
calibrated chart recorder or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording. The sponsor must be notified immediately upon discovery of any excursion from the 
established range. Temperature excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the investigational 
product and will provide supportive documentation as necessary. Under no circumstances should 
the product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
Not Applicable.
6.4
Drug Accountability  
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content, and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All dispensed 
investigational product will be documented on the CRFs and/or other investigational product 
record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.


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The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the mask of the study is not compromised.
With the written agreement of the sponsor, at the end of the study all unused stock and 
empty/used investigational product packaging may be destroyed at the site or a local facility. In 
this case, destruction records identifying what was destroyed as well as when and how must be 
obtained with copies provided to the sponsor. Destruction of investigational products must be in 
accordance with local, state, and national laws.
If a site is not approved by the sponsor to destroy the investigational product, all used and unused 
stock is to be sent to a nominated contractor on behalf of the sponsor. Investigational products 
being returned to the sponsor’s designated contractors must be counted and verified by clinical 
site personnel and the sponsor (or designated contractor research organization [CRO]). Validated 
electronic return systems (ie, IRT) may not require a shipment form. Returned investigational 
products must be packed in a tamper-evident manner to ensure product integrity. Contact the 
sponsor for authorization to return any investigational product prior to shipment. Shipment of all 
returned investigational product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Subjects must be instructed to bring their investigational product and empty/used investigational 
product packaging to every visit. The pharmacist/nominated person will record details on the 
drug accountability form.
Subject compliance will be verified verbally during study visits. In cases of non-compliance, the 
investigator should determine if the medical monitor must be contacted for consultation. 


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7.
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Assessments (see Table 1) and must be referred to in conjunction with the 
instructions provided in this section. Procedures or assessments that are not completed or are 
performed out of order should be captured as protocol deviations.
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject (as per 
local requirements). If a subject is younger than the legal age of consent (per local laws), the 
subject’s parent(s), guardian, or legally authorized representative will provide written informed 
consent; the subject will provide verbal or written assent as appropriate. There must be 
documentation of consent/assent (as per local requirements) indicating that the subject is aware 
of the investigational nature of the study and the required procedures and restrictions, prior to 
performing any study-related procedures. 
Where applicable, all procedures will be performed in both eyes.
7.1.1
Visit 1 (Day 1)
Screening and baseline/randomization will occur at Visit 1 (Day 1 [-1 day]). Visit 1 assessments, 
beginning with informed consent, will be performed as outlined in Table 1.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product. Subjects cannot be rescreened once they have been designated as a 
screen failure.
A urine pregnancy test will be completed for all females of childbearing potential. The results 
will be read by site personnel and recorded in the source documents.
All AEs occurring after signature of informed consent must be recorded in the source documents 
and CRF. 
Prior to randomization, the procedures should be performed in the following order (in both eyes, 
as appropriate):

Informed consent (and assent, if applicable)

Inclusion/exclusion criteria

Medical history

Demographics

Concomitant medications

Urine pregnancy test (for women of childbearing potential)


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
Ocular discomfort scale

BCVA

Slit lamp biomicroscopy

Bulbar conjunctival injection evaluation

Ocular conjunctival discharge evaluation

AdenoPlus® test (if not previously conducted within 24 hours of Visit 1)
If any findings during screening exams do not meet the inclusion/exclusion criteria, the subject is 
not eligible to be randomized. 
Eligible subjects must have a positive response in at least one eye. A positive response is defined 
as meeting ALL of the following criteria in the same eye:

Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤3 days prior to 
Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection 
Scale

Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
Study eye will not be determined at Visit 1. All ophthalmic assessments will be conducted on 
both eyes. Selection of study eye for analyses will be according to the criteria outlined in 
Section 9.8.1.
The procedures should be performed in the following order:

Conjunctival bacterial culture collection (1 swab per eye). An additional swab from each eye 
will be collected in subjects <2 months of age for testing the presence of chlamydia and 
gonorrhea 

Non-dilated/dilated fundus examination

Randomization

Dispense and instill investigational product in both eyes by the designated site staff 
investigational product administrator. The investigational product bottle should be shaken 
well prior to use at each dosing.
All assessments, randomization, and investigational product instillation on Day 1 must take place 
with sufficient time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses).


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7.1.2
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8)
Visits 2 (Day 3 [+1 day]), 3 (Day 5), and 4 (Day 8 [+1 day]) assessments will be performed as 
outlined in Table 1 and as described in the Study Operations Manual. Assessments should be 
performed in descending order as listed.
Subject compliance will be verified verbally during study visits. In cases of non-compliance, the 
investigator should determine if the medical monitor must be contacted for consultation. 
Subjects should not instill investigational product within 12 hours of scheduled study visits. To 
ensure this, subjects should be reminded to not dose the morning of Visits 2, 3, and 4. 
Investigational product instillation should only be performed in-office if it is necessary and 
should be done once all other assessments are completed. Subjects who instill investigational 
product less than 12 hours before study visits will be recorded as protocol deviations.
7.1.3
Visit 5 (End of Study or Early Termination)
Safety follow-up will be conducted at Visit 5 (the end-of-study visit). Visit 5 (Day 12 [+2 days]) 
assessments will be performed as outlined in Table 1. Assessments should be performed in 
descending order as listed.
Subjects who discontinue the study and proceed to Visit 5 for early termination should have 
investigational product collected, a compliance assessment, and drug accountability assessed at 
their final visit.
All AEs and serious AEs (SAEs) that are not resolved at the time of Visit 5 or early termination 
will be followed to closure (see Section 8.1).
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
7.2.1.1
Demographics
Demographic information will be collected at Visit 1. Date of birth (where permitted), age, sex, 
race, and ethnicity will be recorded.
7.2.1.2
Medication and Medical History
Medication History
Refer to Section 5 for full details on collection of prior treatment.
The investigator will categorize treatments as ocular (specified as left eye, right eye, or both 
eyes) or non-ocular-based on the indication for use. Prior treatment information must be recorded 
on the appropriate CRF page. 


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Medical History
The site must record all clinically or medically relevant information regardless of how much time 
has elapsed since the date of any diagnosis. Medical history will be classified as ocular (specified 
as left eye, right eye or both eyes)   or non-ocular by the investigator. History should include but 
is not limited to: 

History of ocular diseases/conditions 

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, and any other non-ocular diseases/underlying conditions within 
the past year prior to the screening visit (Visit 1)
7.2.1.3
AdenoPlus Test
The AdenoPlus test will be performed at Visit 1 (unless results are available from a test 
performed within 24 hours of Visit 1) as outlined in Table 1. A negative result in both eyes is 
required for enrollment in this study.
The AdenoPlus test is an in-office test that allows for the detection of adenoviral antigens 
directly from human eye fluid. A small tear sample is transferred onto the AdenoPlus test, which 
confirms the presence of adenovirus and the viral form of conjunctivitis. 
Please refer to the Study Operations Manual for a detailed description of the AdenoPlus Test and 
administration.
7.2.2
Efficacy
7.2.2.1
Clinical Resolution
Clinical resolution of bacterial conjunctivitis is defined as the absence (score=0) of bulbar 
conjunctival injection and ocular conjunctival discharge in the study eye. Bulbar conjunctival 
injection will be assessed based on a 0-4 scale that uses pictures from the Validated Bulbar 
Redness (VBR) Scale, and ocular conjunctival discharge will be assessed based on a 0-3 scale. 
Details of the bulbar conjunctival injection and ocular conjunctival discharge scales are located 
in the Study Operations Manual.
7.2.2.2
Bacterial Eradication
Bacterial eradication for an eye is defined as absence of all bacterial species present at or above 
pathological threshold at baseline in that eye. 
Pathological threshold for individual bacterial species will be based on colony-forming unit 
(CFU)/mL threshold levels established by Cagle and modified by Leibowitz for different ocular 
bacterial species found in the specimens collected from each subject (Leibowitz, 1991). Bacterial 
species will be determined by Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass 
Spectrometry, using their protein patterns.
Additional details are located in the Study Operations Manual. 


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7.2.3
Safety
Safety assessments will be performed in both eyes.
7.2.3.1
Best Corrected Visual Acuity
The BCVA will be performed prior to slit lamp examination during the study as outlined in 
Table 1. 
The complete instructions for performing the BCVA are in the Study Operations Manual. 
Changes in visual acuity (VA) will be assessed for clinical significance. Clinically significant 
changes should be recorded in the source and on the electronic CRF (eCRF) as an AE.
For subjects who are too young to use an ETDRS chart, use an age-appropriate measurement 
method in accordance with the AAP Policy Statement for Visual System Assessment in Infants, 
Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American Academy of 
Pediatrics, 2016; located in the Study Operations Manual) The policy statement recommends 
formal vision screening can begin at 3 years of age. VA measurements for children under the age 
of 3 will be done at the discretion of the investigator. If not done, child should be able to fixate 
on and follow a moving object. This is not a requirement in subjects <2 months of age since the 
ability does not develop until about 2 months of age. However, if an infant <2 months of age is 
able to fix and follow, it should be recorded. The enrollment of subjects <2 months of age will be 
based on subject qualifying all other eligibility criteria and investigator discretion.
7.2.3.2
Slit Lamp Biomicroscopy
Slit lamp biomicroscopy (or handheld slit lamp) will be performed during the study as outlined 
in Table 1. Magnification of the slit lamp will be consistent with standard clinical practice. The 
subject will be seated.
Observations will be graded as normal or abnormal. Abnormal findings will be described, and 
clinically significant abnormalities should be recorded in the source and on the eCRF (in medical 
history at screening; any changes from the screening visit may be recorded as AEs by the 
investigator). Please note the investigator may use his/her discretion to determine whether not 
clinically significant (NCS) and disease progression should be considered AEs). The following 
will be examined at each visit: 

Lids 

Conjunctiva 

Cornea

Anterior chamber

Iris

Lens


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For infants and young children, if the above exams cannot be performed with a slit lamp or a 
hand held slit lamp, an external examination is to be conducted in accordance with the AAP’s 
Policy Statement for Visual System Assessment in Infants, Children, and Young Adults by 
Pediatricians (Donahue and Baker, 2016; American Academy of Pediatrics, 2016; located in the 
Study Operations Manual). The examination of lens in these subjects should be conducted at 
Visits 1 and 5 (or ET visit) and graded based on the external examination and red reflex exam 
(Section 7.2.3.3). All other structures listed above will be examined and graded at all visits based 
on the external examination. Observations will be graded as normal or abnormal. Abnormal 
findings will be described.
7.2.3.3
Non-dilated/Dilated Fundus Examination
Fundus examination must be conducted after BCVA, slit lamp biomicroscopy, and conjunctival 
swab for bacterial culture has been collected. 
A non-dilated fundus examination will be performed in all subjects with the exception of infants 
and uncooperative small children during the study as outlined in Table 1.
Observations will be graded as normal or abnormal. Abnormal findings will be described.
The following will be examined:

Vitreous

Optic Nerve

Macula
Clinically significant changes should be recorded in the source and on the eCRF as an AE.
If a non-dilated fundus exam is attempted and is not feasible, a dilated fundus exam should be 
conducted. The test should be conducted the same way (either dilated or non-dilated) at both 
Visits 1 and 5 (or ET).
For infants and small children in whom a fundus examination cannot be done, a red reflex exam 
will be conducted in accordance with the AAP Policy Statement for Visual System Assessment 
in Infants, Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American 
Academy of Pediatrics, 2016; located in the Study Operations Manual). Observations will be 
graded as normal or abnormal. Abnormal findings will be described. The red reflex should be 
normal (present and symmetrical for both eyes) at the screening/baseline visit.
7.2.3.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.) Any AE that occurs after the first dose of 
investigational product instillation will be considered a treatment-emergent AE (TEAE).


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Adverse events may also be determined by the investigator during study examinations as 
mentioned in previous sections.
7.2.3.5
Microbiology Laboratory Evaluations
All laboratory assays will be performed according to the laboratory’s normal procedures. 
All bioanalytical assays for the study will be validated following Food and Drug Administration 
(FDA)/International Conference on Harmonisation (ICH) guidelines, based on the method’s 
intended use. The lab will only receive sample identification numbers and collection dates, and 
the lab results will then be transferred to the central lab for data analysis. The lab will not receive 
any information on subject treatment assignment.
One swab sample from inferior conjunctival cul-de-sac of each eye will be collected at all study 
visits for all bacterial testing. An additional sample will be collected from each eye at Visit 1 for 
qualitative detection of herpes simplex virus (HSV). This sample will also be used for PCR 
qualitative detection of chlamydia and gonorrhea in subjects <2 months of age. 
Bacterial eradication as well as antibiotic sensitivity will be determined based on bacterial 
cultures using standard microbiological laboratory procedures. 
7.2.3.6
Pregnancy Test 
A urine pregnancy test is performed on all females of childbearing potential at Visits 1 and 5, or 
if pregnancy is suspected. Urine pregnancy test kits will be provided by the sponsor and read on 
site by qualified site personnel.
7.2.3.7
Health-related Quality of Life Assessments
Ocular discomfort associated with conjunctivitis symptoms will be assessed through the ocular 
discomfort scale (ODS). The ODS is composed of 3 items: pain, itching, and foreign body 
sensation. All items will be evaluated using a 0-10 scale. A separate scale will be administered 
for children younger than 8 years of age. Please see the Study Operations Manual for a detailed 
description of this assessment.


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, and Recording of Adverse 
Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event, including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.


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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.


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8.1.5
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine -hCG 
test or ultrasound result will determine the pregnancy onset date.
8.1.6
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category:

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: This includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol.)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a pre-specified total daily dose of 4 drops per eye of the product. 

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.


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Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reported as a medication 
error.
The administration and/or use of an expired investigational product should be reported as a 
medication error.
In cases of overdose, the investigator should determine if the medical monitor must be contacted 
for consultation.
Please refer to the Study Operations Manual for further details on reporting overdose and 
medication errors. An AE should only be reported if any of these events meets the definition of 
an AE as outlined in Section 8.1.
All investigational product provided to pediatric subjects should be administered or supervised 
by the parent(s)/guardian/legally authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure, which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO/Shire medical monitor 
within 24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see 
Section 8.1.6) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the CRO/Shire medical monitor using the details specified in the emergency 
contact information section of the protocol.


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8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires in-subject hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in in subject 
hospitalization, or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject provides 
written informed consent (and assent, if applicable) until the defined follow-up period stated in 
Section 7.1.3 and must be reported to the Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.


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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and/or the clinical CRO is responsible for notifying the relevant regulatory 
authorities and Institutional Review Boards (IRBs)/ethics committees (ECs) of related, 
unexpected SAEs.
In addition, the sponsor and/or the clinical CRO is responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the SHP640 
program. 
The investigator is responsible for notifying the local IRB, local EC, or relevant local regulatory 
authority of all SAEs that occur at his or her site as required.


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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigator’s authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. 
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRF Completion Guidelines. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unmask the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unmasking, any data that may unmask study team personnel 
will be presented as masked information or otherwise will not be made available. If applicable, 
unmasked data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be addressed.
In addition to a final SAP for the final analysis, a separate SAP for the interim analysis will be 
finalized prior to unmasking and performing the interim analysis. The SAP for the final analysis 
will be finalized prior to unmasking of the study to preserve the integrity of the statistical 
analysis and study conclusions. 


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All final statistical analyses will be performed after the database is locked and unmasked.
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513) Version 
9.2 or higher. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
An unmasked interim analysis (IA) will be performed after ~50% subjects exit the trial in the 
modified intent-to-treat (mITT) population, with data to be analyzed entered into the database, 
queried, and discrepancies resolved. The purpose of the IA will be to assess the adequacy of the 
initial sample size estimation by evaluating conditional power for the primary comparison of 
SHP640 versus placebo on clinical resolution in the treatment of subjects with bacterial 
conjunctivitis in the study eye at Visit 3 (Day 5). There is no intention to stop early for efficacy 
or futility based on the results from the IA. 
The IA will be performed by an external unmasked independent statistician and/or unmasked 
programmers based on a prespecified interim SAP. The interim SAP will explicitly describe how 
the conditional power is to be calculated and the precise rules for altering the sample size 
depending on the potential results. The interim SAP will be finalized prior to IA. The interim 
statistical report including the results will be distributed only to a limited group of people who 
are not involved in the conduct of the trial. All sponsor, CRO, and site staff involved in the 
conduct of the trial must remain masked throughout the trial. Recommendation from the IA to 
increase the sample size may require an amendment to the study protocol. There is no inflation
of type I error from this IA because the sole purpose of the planned IA is to adjust the sample 
size by using the conditional power approach, and the sample size will be changed only under 
certain conditions (Mehta and Pocock, 2011). However, for conservativeness, two-sided 0.0001 
alpha will be spent for the proposed IA and a two-sided alpha of 0.0499 will be used for final 
analyses.
9.6
Sample Size Calculation and Power Considerations
The sample size was estimated for the primary comparison of SHP640 versus placebo on clinical 
resolution in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 
(Day 5) using nQuery Advisor 7.0. Subjects will be randomized 3:1:3 to receive either SHP640, 
PVP-I, or placebo within each age stratum. 
A sample size of 504 subjects (216 subjects in each of the SHP640 and placebo groups, 72 in 
PVP-I group) will ensure ~90% power to compare the SHP640 and placebo treatment groups 
assuming 61% and 45% subjects with clinical resolution, respectively, using Fisher’s Exact test 
at 2-sided 5% level of significance. All efficacy analyses will be based on the mITT with 
post-baseline last observation carried forward for the subjects with missing clinical resolution 
status as Visit 3 (Day 5).
An exploratory PVP-I arm (ie, 72 subjects in mITT and approximately 103 randomized subjects) 
will be included in the trial to provide parameter estimates on PVP-I treatment effect to inform 
future studies. No formal hypothesis testing will be conducted on the PVP-I arm. 


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To ensure 504 subjects in the mITT population, approximately 721 subjects will be randomized 
in this study (approximately 309 subjects in each of SHP640 and placebo groups; approximately 
103 subjects in PVP-I group).
9.7
Study Population
The Safety Population will include all subjects who receive at least 1 dose of investigational 
product.
The Intent-to-Treat (ITT) Population will include all randomized subjects. 
The mITT Population consists of a subset of the ITT population who receive at least 1 dose of 
investigational product and have a positive bacterial culture (presence of 1 or more bacterial 
species at or above pathological threshold) at baseline in the study eye.
9.8
Efficacy Analyses
The analyses on primary, key secondary, secondary, and exploratory efficacy endpoints will be 
performed on the mITT population (unless specified otherwise) and will be presented by 
treatment group. 
Additional sensitivity analyses may be conducted in the ITT population.
For both efficacy and safety analyses, baseline is defined as the assessments taken prior to 
treatment at Visit 1 (Day 1).
9.8.1
Study Eye Designation
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a 
score of at least 1 for both ocular conjunctival discharge and bulbar conjunctival redness at 
baseline (baseline is defined as the assessments taken prior to treatment at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive bacterial culture (presence of 1 
or more bacterial species at or above pathological threshold) at baseline or both eyes eligible 
and both with a non-positive bacterial culture (absence of any bacterial species at or above 
pathological threshold) at baseline, the study eye will be the eye with the highest global 
clinical score (sum of bulbar conjunctival injection and ocular conjunctival discharge) at 
baseline. If both eyes have the same global clinical score at baseline, then the study eye will 
be the right eye. 

For subjects with both eyes eligible with a positive bacterial culture in 1 eye at baseline, the 
baseline bacterial culture positive eye will be the study eye. 

For subjects with only 1 eligible eye, the eligible eye will be the study eye irrespective of its 
baseline bacterial culture result. 


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The study eye designation is summarized in the table below:
Eligible Eye(s)
Bacterial Culture Results
Study Eye
Both eyes
Both eyes positive
Highest global clinical score at Visit 1 (Day 1)
(or right eye if scores are the same)
Both eyes
Both eyes negative
Highest global clinical score at Visit 1 (Day 1)
(or right eye if scores are the same)
Both eyes
One eye positive
The bacterial culture positive eye at Visit 1 (Day 1) 
One eye
Positive or negative for either eye
The eligible eye 
9.8.2
Primary Efficacy Endpoint
The primary efficacy endpoint is clinical resolution status (defined as absence [ie, a score of 0] 
of bulbar conjunctival injection and ocular conjunctival discharge) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo.
All efficacy analyses will be performed on the mITT population and presented by treatment 
groups. There is a single primary comparison for the single primary endpoint. Therefore, no 
adjustment of multiplicity is needed for the hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 5) will be 
compared between the SHP640 and placebo group. The comparison will be based on the 
proportion of subjects with clinical resolution in the study eye at Visit 3 (Day 5) using Fisher’s 
Exact test at 2-sided 0.0499 significance level. 
If subjects have missing clinical resolution status at Visit 3 (Day 5), then the last post-baseline 
observation will be carried forward for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with 
clinical resolution in the study eye between SHP640 ophthalmic solution and placebo with the 
alternative of the non-zero difference in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 2-sided Fisher’s Exact 
test at 4.99% level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical 
method(s) including other methods of imputation of missing data. Sensitivity analyses may be 
conducted in the ITT population in addition to the mITT. In addition, descriptive statistics will 
be generated for the primary efficacy endpoint by treatment within the overall pediatric 
population (ie, birth to 18 years) and within each pediatric age stratum (<6 years and 6 to 
<18 years) in mITT. A detailed plan for primary analysis including additional sensitivity 
analyses will be described in the SAP.


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9.8.3
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoint is bacterial eradication status (defined as absence of all 
bacterial species present at or above pathological threshold at baseline) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo.
All efficacy analyses will be performed on the mITT population and presented by treatment 
groups. In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary 
hypotheses will be tested sequentially. Each hypothesis will be tested using Fisher’s Exact test at 
2-sided 4.99% level with null hypothesis of no difference in the proportion of subjects for the 
endpoint between the 2 treatment groups. 
First, the primary efficacy endpoint will be tested. Only if the null hypothesis for the primary 
efficacy endpoint is rejected at 4.99% level, then the key secondary efficacy endpoint of bacterial 
eradication will be tested to compare the proportion of subjects with bacterial eradication 
between the SHP640 and placebo treatment group. If subjects have missing bacterial eradication 
status at Visit 3 (Day 5), then the last post-baseline observation will be carried forward for the 
determination of bacterial eradication of the study eye. 
Sensitivity analyses will also be done on key secondary efficacy endpoints using similar methods 
as described above. In addition, descriptive statistics will be generated for the key secondary 
efficacy endpoint by treatment within the overall pediatric population (ie, birth to 18 years) and 
within each pediatric age stratum (<6 years and 6 to <18 years) in the mITT. Details on the 
analyses will be described in the SAP.
9.8.4
Secondary Efficacy Endpoints
All secondary efficacy analyses will be performed on the mITT population and presented by 
treatment group. No hypothesis testing is planned for the secondary efficacy endpoints. All 
secondary efficacy endpoint will be summarized by treatment groups using descriptive statistics 
at each assessment visit. Continuous endpoints will be summarized by number of subjects (n), 
mean, median, standard deviation, minimum, maximum, and confidence intervals (CIs). Binary 
endpoints will be summarized by number of subjects (n), frequencies, proportions, and CIs. Time 
to event endpoint will be summarized by Kaplan-Meier survival estimates.
Secondary efficacy endpoints are defined as follows:

Clinical resolution status of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12) in the study eye

Bacterial eradication status (defined as absence of all bacterial species present at or above 
pathological threshold at baseline) as assessed by bacterial culture at Visits 2 (Day 3), 4 
(Day 8), and 5 (Day 12) in the study eye

Absolute and change from baseline of the individual clinical signs score (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12) in the study eye


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
The global clinical score (defined as the sum of bulbar conjunctival injection and ocular 
conjunctival discharge) and change from baseline in the global clinical score at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with 
neither injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), 
and 5 (Day 12) in the study eye

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), 
and 5 (Day 12) in the study eye

Use of rescue medication
9.8.5
Exploratory Efficacy Endpoints
The ocular discomfort endpoints will be evaluated by absolute and change from baseline of 
ocular discomfort scores (or by the binary ocular discomfort endpoint for children younger than 
8 years of age) due to conjunctivitis symptoms at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12) (mITT population and ITT population). 
No hypothesis testing is planned for the exploratory efficacy endpoint. Exploratory endpoints 
will be summarized using methods similar to secondary endpoints.
9.9
Safety Analyses
Safety data will be presented for the safety population by treatment group and overall.
Safety data collected at baseline prior to treatment (Visit 1/Day 1) will be used as the baseline 
value for safety analysis.
Adverse events, including those suggestive of any local tolerability issues, will be coded using 
the Medical Dictionary for Regulatory Activities. The number of subjects and percentage with a 
TEAE as well as the number of TEAEs will be calculated overall, by system organ class, by 
preferred term, and by treatment group. Treatment-emergent adverse events will be further 
summarized by severity and relationship to investigational product. Adverse events related to 
investigational product, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized and listed.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or a 
non-ocular AE.


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The following safety endpoints will be descriptively summarized by treatment group at each 
applicable visit:

BCVA

Slit lamp biomicroscopy

Lid 

Conjunctiva 

Cornea 

Anterior chamber 

Iris

Lens 

Non-dilated/dilated fundus examination

Vitreous 

Optic nerve 

Macula 

Urine pregnancy testing (for females of childbearing potential)
9.10
Other Analyses
No other analyses are planned in this study.


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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, European Union 
(EU) Directive 2001/20/EC and its updates, and local ethical and legal requirements.
In case of substantial amendment, approval from the Competent Regulatory Authority will be 
sought before implementation. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC and its updates, as well as all applicable national and local laws and 
regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.


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10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study that has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC and its updates, and applicable regulatory requirements and 
guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 


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The coordinating principal investigator will be assigned and selected based on the extent of their 
involvement in the study and experience in the therapeutic area.
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs to ensure accurate and timely information is provided at all 
phases during the study may be done by the sponsor, applicable CRO, investigator, or, for 
multicenter studies, coordinating principal investigator according to national provisions and will 
be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data. All corrections to the eCRF must indicate the reason for 
change. If corrections are made after the review and signature by the investigator, he or she must 
be made aware of the change, and his or her awareness must be documented by re-signing the 
eCRF.   
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include but are not limited to the 
subject’s medical file, scales, ODS, and documented results of AdenoPlus test results.


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All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) will check the CRF 
entries against the source documents. The consent form includes a statement by which the
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
European Medicines Agency (EMA), United Kingdom Medicines and Healthcare products 
Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation, or honoraria; any proprietary interest in investigational product; and any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. 


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Each subject or the subject’s legally authorized representative, as applicable, is requested to sign 
and date the subject informed consent form or a certified translation if applicable, after the 
subject has received and read (or been read) the written subject information and received an 
explanation of what the study involves, including but not limited to the objectives, potential 
benefits and risk, inconveniences, and subject’s rights and responsibilities. A copy of the 
informed consent and assent documentation (ie, a complete set of subject information sheets and 
fully executed signature pages) must be given to the subject or the subject’s legally authorized 
representative, as applicable. This document may require translation into the local language. 
Signed consent forms must remain in each subject’s study file and must be available for 
verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent(s)/guardian/legally authorized representative/caregiver of the safe, responsible 
storage and administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form and assent form, 
where applicable, that was reviewed by the IRB/EC and received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents.


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For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the CRO.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP640; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, other information (eg, initials and 
date of birth if the local law permits) may also be collected and used to assist the sponsor to 
verify the accuracy of the data (eg, to confirm that laboratory results have been assigned to the 
correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to 
and used in other countries that may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.


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All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.


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11.
REFERENCES
American Academy of Pediatrics 2016. Visual system assessment in infants, children, and young 
adults by pediatricians. Pediatrics, 137, 28-30.
Azari, A. A. & Barney, N. P. 2013. Conjunctivitis: a systematic review of diagnosis and 
treatment. Jama, 310, 1721-9.
Betadine 2004. Betadine Prescribing Information.
Capriotti, J. A., Stewart, K. P. & Pelletier, J. 2010. The unique challenges of viral conjunctivitis -
Its similarities to bacterial infection belie key differences that impact clinical care 
[Online]. Ophthalmology Management. Available: 
http://www.ophthalmologymanagement.com/articleviewer.aspx?articleid=104651.
CDC. 2010. Conjunctivitis (pink eye) [Online]. Centers for Disease Control and Prevention. 
Available: http://www.cdc.gov/conjunctivitis/clinical.html.
Chen, C. J. & Starr, C. E. 2008. Epidemiology of gram-negative conjunctivitis in neonatal 
intensive care unit patients. Am J Ophthalmol, 145, 966-970.e2.
Dias, C., Gonçalves, M. & João, A. 2013. Epidemiological study of hospital-acquired bacterial 
conjunctivitis in a level III neonatal unit. Sci World J, 1-5.
Donahue, S. P. & Baker, C. N. 2016. Procedures for the Evaluation of the Visual System by 
Pediatricians. Pediatrics, 137.
Ford, E., Nelson, K. E. & Warren, D. 1987. Epidemiology of epidemic keratoconjunctivitis. 
Epidemiol Rev, 9, 244-61.
Gordon, Y. J., Gordon, R. Y., Romanowski, E. & Araullo-Cruz, T. P. 1993. Prolonged recovery 
of desiccated adenoviral serotypes 5, 8, and 19 from plastic and metal surfaces in vitro. 
Ophthalmology, 100, 1835-9; discussion 1839-40.
Haas, J., Larson, E., Ross, B., See, B. & Saiman, L. 2005. Epidemiology and diagnosis of 
hospital-acquired conjunctivitis among neonatal intensive care unit patients. Pediatr 
Infect Dis J, 24, 586-589.
Leibowitz HM. Antibacterial effectiveness of ciprofloxacin 0.3% ophthalmic solution in the 
treatment of bacterial conjunctivitis. Am J Ophthalmol. 1991 Oct;112(4 Suppl):29S-33S.
Maxidex 2007. Maxidex Prescribing Information.
Mehta, C. R. & Pocock, S. J. 2011. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Statistics in medicine, 30, 3267-84.
Nauheim, R. C., Romanowski, E. G., Araullo-Cruz, T., Kowalski, R. P., Turgeon, P. W., Stopak, 
S. S. & Gordon, Y. J. 1990. Prolonged recoverability of desiccated adenovirus type 19 
from various surfaces. Ophthalmology, 97, 1450-3.
O'Brien, T. P., Jeng, B. H., McDonald, M. & Raizman, M. B. 2009. Acute conjunctivitis: truth 
and misconceptions. Curr Med Res Opin, 25, 1953-61.
Patel, P. B., Diaz, M. C. G., Bennett, J. E. & Attia, M. W. 2007. Clinical features of bacterial 
conjunctivitis in children. Clin Investigations, 1-5.
Pelletier, J. S., Stewart, K., Trattler, W., Ritterband, D. C., Braverman, S., Samson, C. M., Liang, 
B. & Capriotti, J. A. 2009. A combination povidone-iodine 0.4%/dexamethasone 0.1% 
ophthalmic suspension in the treatment of adenoviral conjunctivitis. Adv Ther, 26, 776-
83.


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Pelletier, M. R., Casella, L. G., Jones, J. W., Adams, M. D., Zurawski, D. V., Hazlett, K. R., Doi, 
Y. & Ernst, R. K. 2013. Unique structural modifications are present in the 
lipopolysaccharide from colistin-resistant strains of Acinetobacter baumannii. Antimicrob 
Agents Chemother, 57, 4831-40.
Pocock, S. J. & Simon, R. 1975. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 31, 103-15.
Rours, I. G. I. J. G., Hammerschlag, M. R., Ott, A., De Faber, T. J. T. H. N., Verbrugh, H. A., de 
Groot, R. & Verkooyen, R. P. 2008. Chlamydia trachomatis as a cause of neonatal 
conjunctivitis in Dutch infants. Pediatrics, 121, e321.
Statham, M. O., Sharma, A. & Pane, A. R. 2008. Misdiagnosis of acute eye diseases by primary 
health care providers: incidence and implications. Med J Aust, 189, 402-4.
Visscher, K. L., Hutnik, C. M. & Thomas, M. 2009. Evidence-based treatment of acute infective 
conjunctivitis: Breaking the cycle of antibiotic prescribing. Can Fam Physician, 55,
1071-5.


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12.
APPENDICES




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APPENDIX 2
SCALES AND ASSESSMENTS
All scales assessments referenced in the protocol, including procedural instructions for the 
investigator, are in the Study Operations Manual and the Laboratory Manual (provided upon 
request).

Prot_002.pdf: 
PROTOCOL SHP640-303
TITLE:
A Phase 3, Multi-center, Randomized, Double-Masked Study to 
Evaluate the Clinical Efficacy and Safety of SHP640 (PVP-Iodine 0.6% 
and Dexamethasone 0.1%) Ophthalmic Suspension Compared to 
Placebo in the Treatment of Bacterial Conjunctivitis
DRUG:
SHP640
IND:
75,723
EUDRACT NO:
2016-003361-25
SPONSOR:
Shire
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 27 September 2016
Amendment 1: 28 November 2016
Amendment 2: 15 February 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire




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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to the Shire Global Pharmacovigilance and Risk Management 
Department. Applicable fax numbers and e-mail address can be found on the form (sent under 
separate cover). A copy of this form must also be sent to the contract research organization 
(CRO)/Shire medical monitor by fax or e-mail using the details below.
Fax: 
Email: 
For protocol- or safety-related issues in the United States (US) and North American region, 
the investigator must contact the Shire medical monitor:
 MBBS, DPM, MS
Primary telephone number: 
Fax: 
Alternate number:
For protocol- or safety-related issues in regions other than North America, the investigator 
must contact the Quintiles 24/7 Emergency Contact center:
Primary telephone number: 
 
Alternate number: 


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA), 


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
TABLE OF CONTENTS.................................................................................................................5
LIST OF TABLES...........................................................................................................................9
LIST OF FIGURES .........................................................................................................................9
LIST OF APPENDICES..................................................................................................................9
1.
BACKGROUND INFORMATION.......................................................................................21
1.1
Indication and Current Treatment Options...............................................................21
1.2
Product Background and Clinical Information ........................................................21
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................22
2.1
Rationale for the Study.............................................................................................22
2.2
Study Objectives ......................................................................................................22
2.2.1
Primary Objective..................................................................................................22
2.2.2
Key Secondary Objective ......................................................................................22
2.2.3
Secondary Objectives.............................................................................................22
2.2.4
Exploratory Objectives ..........................................................................................23
3.
STUDY DESIGN ...................................................................................................................23
3.1
Study Design and Flow Chart ..................................................................................23
3.2
Duration and Study Completion Definition .............................................................24
3.3
Sites and Regions .....................................................................................................24
4.
STUDY POPULATION.........................................................................................................24
4.1
Inclusion Criteria......................................................................................................25
4.2
Exclusion Criteria.....................................................................................................25
4.3
Reproductive Potential .............................................................................................27
4.3.1
Female Contraception............................................................................................27
4.4
Discontinuation of Subjects .....................................................................................28
4.4.1
Reasons for Discontinuation..................................................................................29
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................29
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................29
5.1
Prior Treatment ........................................................................................................30
5.2
Concomitant Treatment............................................................................................30
5.2.1
Permitted Treatment...............................................................................................30
5.2.2
Prohibited Treatment .............................................................................................30
6.
INVESTIGATIONAL PRODUCT ........................................................................................31


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6.1
Identity of Investigational Product...........................................................................31
6.1.1
Masking the Treatment Assignment ......................................................................31
6.1.2
Commercially Obtained Investigational Product...................................................31
6.2
Administration of Investigational Product(s)...........................................................31
6.2.1
Interactive Response Technology for Investigational Product Management ........31
6.2.2
Allocation of Subjects to Treatment ......................................................................31
6.2.3
Dosing....................................................................................................................32
6.2.4
Unmasking the Treatment Assignment..................................................................32
6.3
Labeling, Packaging, Storage, and Handling ...........................................................33
6.3.1
Labeling .................................................................................................................33
6.3.2
Packaging...............................................................................................................33
6.3.3
Storage ...................................................................................................................33
6.3.4
Special Handling....................................................................................................34
6.4
Drug Accountability.................................................................................................34
6.5
Subject Compliance..................................................................................................35
7.
STUDY PROCEDURES........................................................................................................36
7.1
Study Schedule.........................................................................................................36
7.1.1
Visit 1 (Day 1) .......................................................................................................36
7.1.2
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8) ............................................................38
7.1.3
Visit 5 (End of Study or Early Termination) .........................................................38
7.1.4
Additional Care of Subjects after the Study ..........................................................38
7.2
Study Evaluations and Procedures ...........................................................................38
7.2.1
Demographic and Other Baseline Characteristics .................................................38
7.2.1.1
Demographics.........................................................................................38
7.2.1.2
Medication and Medical History............................................................38
7.2.1.3
AdenoPlus Test ......................................................................................39
7.2.2
Efficacy..................................................................................................................39
7.2.2.1
Clinical Resolution.................................................................................39
7.2.2.2
Bacterial Eradication..............................................................................39
7.2.3
Safety .....................................................................................................................40
7.2.3.1
Best Corrected Visual Acuity.................................................................40
7.2.3.2
Slit Lamp Biomicroscopy.......................................................................40
7.2.3.3
Non-dilated/Dilated Fundus Examination..............................................41
7.2.3.4
Adverse Event Collection.......................................................................41
7.2.3.5
Microbiology Laboratory Evaluations ...................................................42
7.2.3.6
Pregnancy Test .......................................................................................42
7.2.3.7
Health-related Quality of Life Assessments...........................................42
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................42


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8.1
Definition of Adverse Events, Period of Observation, and Recording of 
Adverse Events.........................................................................................................42
8.1.1
Severity Categorization..........................................................................................43
8.1.2
Relationship Categorization...................................................................................43
8.1.3
Outcome Categorization ........................................................................................44
8.1.4
Symptoms of the Disease Under Study .................................................................44
8.1.5
Pregnancy...............................................................................................................44
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................45
8.2
Serious Adverse Event Procedures ..........................................................................46
8.2.1
Reference Safety Information................................................................................46
8.2.2
Reporting Procedures.............................................................................................46
8.2.3
Serious Adverse Event Definition .........................................................................46
8.2.4
Serious Adverse Event Collection Time Frame.....................................................47
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................47
8.2.6
Fatal Outcome........................................................................................................47
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................48
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................48
9.1
Data Collection.........................................................................................................48
9.2
Clinical Data Management.......................................................................................48
9.3
Data Handling Considerations..................................................................................48
9.4
Statistical Analysis Process......................................................................................49
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......49
9.6
Sample Size Calculation and Power Considerations................................................50
9.7
Study Population ......................................................................................................50
9.8
Efficacy Analyses.....................................................................................................50
9.8.1
Study Eye Designation...........................................................................................51
9.8.2
Primary Efficacy Endpoint ....................................................................................51
9.8.3
Key Secondary Efficacy Endpoints .......................................................................52
9.8.4
Secondary Efficacy Endpoints...............................................................................52
9.8.5
Exploratory Efficacy Endpoints.............................................................................53
9.9
Safety Analyses........................................................................................................53
9.10
Other Analyses .........................................................................................................54
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................54
10.1
Sponsor’s Responsibilities .......................................................................................55
10.1.1 Good Clinical Practice Compliance.......................................................................55
10.1.2 Indemnity/Liability and Insurance.........................................................................55
10.1.3 Public Posting of Study Information......................................................................55


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10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................55
10.1.5 Study Suspension, Termination, and Completion..................................................56
10.2
Investigator’s Responsibilities .................................................................................56
10.2.1 Good Clinical Practice Compliance.......................................................................56
10.2.2 Protocol Adherence and Investigator Agreement..................................................56
10.2.3 Documentation and Retention of Records.............................................................57
10.2.3.1
Case Report Forms.................................................................................57
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................57
10.2.3.3
Audit/Inspection.....................................................................................58
10.2.3.4
Financial Disclosure...............................................................................58
10.3
Ethical Considerations..............................................................................................58
10.3.1 Informed Consent...................................................................................................58
10.3.2 Institutional Review Board or Ethics Committee..................................................59
10.4
Privacy and Confidentiality......................................................................................59
10.5
Study Results/Publication Policy .............................................................................60
11. REFERENCES .......................................................................................................................62
12. APPENDICES ........................................................................................................................64


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LIST OF TABLES
Table 1
Schedule of Assessments .........................................................................................19
Table 2 Common Excluded Treatments and Associated Washout Periods ..........................30
LIST OF FIGURES
Figure 1 SHP640-303 Study Design.......................................................................................24
LIST OF APPENDICES
Appendix 1
Protocol History .....................................................................................65
Appendix 2
Scales and Assessments .........................................................................66


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LIST OF ABBREVIATIONS
AAP
American Academy of Pediatrics
AE
adverse event
BCVA
best corrected visual acuity
CFU
colony-forming unit
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
EC
ethics committee
eCRF
electronic case report form
EMA
European Medicines Agency
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
HSV
Herpes Simplex Virus
IA
interim analysis
ICH
International Conference on Harmonisation
IMP
investigational medicinal product
IOP
intraocular pressure
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
mITT
modified intent-to-treat
MRSA
methicillin-resistant Staphylococcus aureus
NCS
not clinically significant
NF
National Formulary
ODS
ocular discomfort scale
PVP-I
povidone-iodine
QID
4 times a day
SAE
serious adverse event


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SAP
statistical analysis plan
TEAE
treatment-emergent adverse event
US
United States
USP
United States Pharmacopeia
VA
visual acuity
VBR
Validated Bulbar Redness


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STUDY SYNOPSIS
Protocol number: SHP640-303
Drug: SHP640
Title of the study: A Phase 3, Multi-center, Randomized, Double-Masked Study to Evaluate the Clinical Efficacy 
and Safety of SHP640 (PVP-Iodine 0.6% and Dexamethasone 0.1%) Ophthalmic Suspension Compared to Placebo 
in the Treatment of Bacterial Conjunctivitis
Number of subjects (total and for each treatment arm):
Total subjects: Approximately 721
SHP640 treatment arm: Approximately 309
Povidone-iodine (PVP-I) treatment arm: Approximately 103
Placebo treatment arm: Approximately 309 
Investigator(s): multicenter study
Site(s) and Region(s): 
The study will be conducted in approximately 90 sites across North America, South America, Asia/Pacific, Europe, 
the Middle East and Africa.
Study period (planned):
December 2016 to March 2018
Clinical phase:
3
Objectives:
Primary:
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical resolution (defined as 
absence of bulbar conjunctival injection and ocular conjunctival discharge) compared with placebo in the treatment 
of subjects with bacterial conjunctivitis in the study eye at Visit 3 (Day 5). 
Secondary:
The key secondary objective of this study is to evaluate the efficacy of SHP640 based on bacterial eradication 
(defined as absence of all bacterial species present at or above pathological threshold at baseline) compared with 
placebo in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 (Day 5).
Secondary objectives of this study are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints:

Clinical resolution of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12)

Bacterial eradication at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12)

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival injection and ocular 
conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

The global clinical score (sum of bulbar conjunctival injection and ocular conjunctival discharge) and change 
from baseline in the global clinical score at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12)

Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither injection nor 
discharge having a score of 2 at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the treatment of subjects 


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with bacterial conjunctivitis

Use of rescue medication
Rationale:
The clinical presentation of conjunctivitis is often nonspecific, and differential diagnosis of different types of 
conjunctivitis can be challenging (Azari and Barney 2013; O’Brien et al. 2009). Diagnostic testing to differentiate 
the underlying cause of infection is rarely performed in a clinical setting; misdiagnosis can occur in up to 50% of 
cases, which often results in improper antibiotic treatment (Visscher et al. 2009). Incorrect treatment can not only 
increase healthcare costs from unnecessary antibiotic prescriptions and repeat office visits but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or methicillin-resistant Staphylococcus 
aureus). In addition, there is also a risk of overuse and misuse of antibiotics, which are ineffective in the treatment 
of viral infections (Statham et al. 2008). An unmet medical need therefore exists for a safe and efficacious treatment 
that addresses both bacterial and adenoviral conjunctivitis, 2 of the leading causes of acute infectious conjunctivitis. 
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, with 
dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious and inflammatory 
components of adenoviral and bacterial conjunctivitis.
Investigational product, dose, and mode of administration:
The drug product is SHP640 (0.1% dexamethasone and 0.6% PVP-I) ophthalmic suspension.
The comparators are placebo ophthalmic solution and 0.6% PVP-I ophthalmic solution.
Subjects will instill 1 drop of investigational product in each eye 4 times daily (with a minimum of 2 hours between 
doses) for 7 days.
Methodology:
Once screening and baseline assessments are complete and subjects are confirmed eligible to enroll in the study, 
subjects will be randomized, and investigational product will be administered on the same day (Day 1). The first 
dose will be administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a 
day for 7 days. Additional visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). The study 
will last up to 13 days. 
Inclusion and exclusion criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions (by 
the parent(s), guardian, or legally authorized representative, if applicable).
2.
Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), guardian, or 
legally    authorized representative(s) informed consent (and assent, if applicable) to participate in the 
study.
3.
Subjects of any age at Visit 1 (Note: subjects <3 months of age at Visit 1 must have been full-term, ie 
≥37 weeks gestational age at birth).
4.
Have a negative AdenoPlus® test in both eyes within 24 hours of Visit 1 or at Visit 1.
5.
Have a clinical diagnosis of suspected bacterial conjunctivitis in at least 1 eye confirmed by the 
presence of the following minimal clinical signs and symptoms in that same eye:
5.1. Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤3 days prior to Visit 1
5.2. Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection Scale
5.3. Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale


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6.
Be willing to discontinue contact lens wear for the duration of the study.
7.
Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as measured using 
an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will be assessed by an age 
appropriate method in accordance with the AAP Policy Statement for Visual System Assessment in 
Infants, Children, and Young Adults by Pediatricians (Donahue and Baker 2016; American Academy 
of Pediatrics 2016). The policy statement recommends formal vision screening can begin at 3 years of 
age. VA measurements for children under the age of 3 will be done at the discretion of the investigator. 
If not done, child should be able to fixate on and follow a moving object, except subjects <2 months of 
age who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion of 
investigator.  
8.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of non-childbearing potential.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1.
Current or recurrent disease that could affect the action, absorption, or disposition of the 
investigational product, or clinical or laboratory assessments, per investigator’s discretion.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may make the 
subject unlikely to fully complete the study, or any condition that presents undue risk from the 
investigational product or procedures.
3.
Have known or suspected intolerance or hypersensitivity to the investigational product, closely related 
compounds, or any of the stated ingredients. 
4.
Prior enrollment in a FST-100 or SHP640 clinical study.
5.
Subjects who are employees, or immediate family members of employees (who are directly related to 
study conduct), at the investigational site.
6.
Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned for the 
period of the study.
7.
Have a preplanned overnight hospitalization during the period of the study.
8.
Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, iritis, 
ulcerative keratitis, chronic blepharoconjunctivitis), other than bacterial conjunctivitis.
9.
Have active or a history of ocular herpes.
10. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with the 
diagnosis of ocular allergy, toxic conjunctivitis, or non-bacterial ocular infection (eg, viral, fungal, 
acanthamoebal, other parasitic). 
11. Neonates or infants (ie. subjects less than 12 months of age) who have suspected or confirmed (based 
on the result of any test conducted prior to screening) conjunctivitis of gonococcal, chlamydial, 
herpetic or chemical origin.
12. Neonates or infants (ie. subjects less than 12 months of age) whose birth mothers had any sexually 
transmitted disease within 1 month of delivery or any history of genital herpes.
13. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
14. Presence of any significant ophthalmic condition (eg, Retinopathy of Prematurity, congenital cataract, 
congenital glaucoma) or other congenital disorder with ophthalmic involvement that could affect study 
variables.
15. Be a known intraocular pressure (IOP) steroid responder, have a known history of glaucoma, be a 
glaucoma suspect, or have a known history of an elevated IOP >21 mmHg.


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16. Have any known clinically significant optic nerve defects. 
17. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to previous corneal 
trauma or dry eye syndrome; presence of corneal epithelial defect or any significant corneal opacity at Visit 
1.
18. Presence of significant, active condition in the posterior segment that requires invasive treatment (eg, 
intravitreal treatment with vascular endothelial growth factor inhibitors or corticosteroids) and may 
progress during the study participation period. 
19. Have used any topical ocular or systemic antibiotics within ≤7 days of enrollment. 
20. Have used any topical ocular non-steroidal anti-inflammatory drugs within ≤1 day of enrollment.
21. Have used any topical ophthalmic steroids in the last ≤14 days.
22. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 days 
prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no anticipated change in 
dose for the duration of the study. Topical dermal steroids are allowed except in the periocular area.
23. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
24. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all topical 
ophthalmic products for the duration of the study. Use of hot or cold compresses is also not permitted 
during the study.  
25. Have any significant ocular disease (eg, Sjogren’s syndrome) or any uncontrolled systemic disease or 
debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted diseases/infections, 
diabetes, or cystic fibrosis) that may affect the study parameters, per investigator’s discretion.
26. Any known history of immunodeficiency disorder or known active conditions predisposing to 
immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of active 
hepatitis A (anti-hepatitis A virus immunoglobulin M), or organ or bone marrow transplantation.
27. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study.
Maximum duration of subject involvement in the study:
Subject participation will last up to 13 days.
Screening, randomization, and the first treatment administration will occur at Visit 1 (Day 1). 
Additional visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). 
All follow-up procedures will be conducted at Visit 5 (Day 12).
Endpoints and statistical analysis:
Primary Efficacy Endpoint:
Clinical resolution status (defined as absence of bulbar conjunctival injection and ocular conjunctival discharge) in 
the study eye at Visit 3 (Day 5) between SHP640 and placebo.
Key Secondary Efficacy Endpoints:
Bacterial eradication status (defined as absence of all bacterial species present at or above pathological threshold at 
baseline) in the study eye at Visit 3 (Day 5) between SHP640 and placebo.
Secondary Efficacy Endpoints:


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
Clinical resolution status of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) in the study 
eye

Bacterial eradication status (defined as absence of all bacterial species present at or above pathological 
threshold at baseline) as assessed by bacterial culture at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) in the study 
eye 

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival injection and ocular 
conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye 

The global clinical score (defined as the sum of bulbar conjunctival injection and ocular conjunctival discharge) 
and change from baseline in the global clinical score at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in 
the study eye 

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12) in the study eye 

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with neither injection nor 
discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye 

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in 
the study eye 

Use of rescue medication 
Safety Endpoints:

BCVA

Slit lamp biomicroscopy 

Non-dilated/dilated fundus examination

Urine pregnancy testing (for females of childbearing potential)

Adverse events (AEs)
Statistical Methods:
The analyses on primary, key secondary, secondary, and exploratory efficacy endpoints will be performed on the 
modified intent-to-treat (mITT) population (unless specified otherwise) and will be presented by treatment group. 
Additional sensitivity analyses may be conducted on the intent-to-treat (ITT) population. Safety analyses will be 
conducted on the safety population.
For both efficacy and safety analyses, baseline is defined as the assessments taken prior to treatment at Visit 1 (Day 
1).
Analysis Populations:
The safety population will include all subjects who receive at least 1 dose of investigational product.
The ITT population will include all randomized subjects. 
The mITT population consists of a subset of the ITT population who receive at least 1 dose of investigational 
product and have a positive bacterial culture (presence of 1 or more bacterial species at or above pathological 
threshold) at baseline in the study eye.
Designation of Study Eye:
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a score of at least 1 for 
both ocular  conjunctival discharge and bulbar conjunctival redness at baseline (baseline is defined as the 
assessments taken prior to treatment at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive bacterial culture (presence of 1 or more bacterial 
species at or above pathological threshold) at baseline or both eyes eligible and both with a non-positive 


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bacterial culture (absence of any bacterial species at or above pathological threshold) at baseline, the study eye 
will be the eye with the highest global clinical score (sum of bulbar conjunctival injection and ocular 
conjunctival discharge) at baseline. If both eyes have the same global clinical score at baseline, then the study 
eye will be the right eye.

For subjects with both eyes eligible with a positive bacterial culture in one eye at baseline, the baseline bacterial 
culture positive eye will be the study eye.

For subjects with only 1 eligible eye, the eligible eye will be the study eye irrespective of its baseline bacterial 
culture status.
Primary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. There is a single primary 
comparison for the single primary endpoint. Therefore, no adjustment of multiplicity is needed for the hypothesis 
testing for the primary objective.
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 5) will be compared between the 
SHP640 and placebo group. The comparison will be based on the proportion of subjects with clinical resolution in 
the study eye at Visit 3 (Day 5) using Fisher’s Exact test at 2-sided 0.05 significance level.
If subjects have missing clinical resolution status at Visit 3 (Day 5), then the last post-baseline observation will be 
carried forward for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with clinical resolution in the 
study eye between SHP640 ophthalmic Solution and placebo with the alternative of the non-zero difference in the 
proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 2-sided Fisher’s Exact test at 5% level of 
significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical method(s) including 
methods of imputation of missing data. Sensitivity analyses may be conducted in the ITT in addition to the mITT.
Key Secondary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. The key secondary efficacy 
endpoint of this study is bacterial eradication status in the study eye at Visit 3 (Day 5) between SHP640 and placebo. 
In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary hypotheses will be tested 
sequentially. Each hypothesis will be tested using Fisher’s Exact test at 2-sided 5.0% level with null hypothesis of 
no difference in the proportion of subjects for the endpoint between the 2 treatment groups. 
First, the primary efficacy endpoint will be tested. Only if the null hypothesis for the primary efficacy endpoint is 
rejected at 5.0% level, then the key secondary efficacy endpoint of bacterial eradication will be tested to compare 
the proportion of subjects with bacterial eradication between the SHP640 and placebo treatment group. If subjects 
have missing bacterial eradication at Visit 3 (Day 5), then the last post-baseline observation will be carried forward 
for the determination of bacterial eradication of the study eye. 
Sensitivity analyses will also be done on the key secondary efficacy endpoint using similar methods as described 
above.
Secondary Efficacy Analyses:
No hypothesis testing is planned for the secondary efficacy endpoints. All secondary efficacy endpoints will be 
summarized by treatment groups using descriptive statistics at each assessment visit. Continuous endpoints will be 
summarized by number of subjects (n), mean, median, standard deviation, minimum, maximum, and confidence 
intervals (CIs). Binary endpoints will be summarized by number of subjects (n), frequencies, proportions, and CIs. 
Time to event endpoint will be summarized by Kaplan-Meier survival estimates.
Safety Analyses:
Safety data will be presented for the safety population by treatment group and overall.


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Safety data collected at baseline prior to treatment (Visit 1/Day 1) will be used as the baseline value for safety 
analysis. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The number of subjects and 
percentage with a treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated 
overall, by system organ class, by preferred term, and by treatment group and overall. TEAEs will be further 
summarized by severity and relationship to investigational product. AEs related to investigational product, AEs 
leading to withdrawal, serious AEs, and deaths will be similarly summarized and listed. Any AE that occurs after the 
first dose of investigational product instillation will be considered a TEAE.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or a non-ocular AE.
Slit lamp biomicroscopy, non-dilated/dilated fundus exam, BCVA, and urine pregnancy test (for females of 
childbearing potential) will be descriptively summarized by treatment group and overall at each applicable visit.


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Study Schedule
Table 1
Schedule of Assessments
Procedure
(All ocular assessments and 
procedures performed bilaterally)
Visit 1
Screeninga and 
Baseline
(Day 1)
-1 Day
Visit 2
(Day 3)
Visit 3
(Day 5)
Visit 4
(Day 8)
Visit 5b
(Day 12)
+1 Day
Informed consent/assenta
X
Inclusion/exclusion criteriaa
X
Medical history 
X
Demographics
X
Concomitant medications
X
X
X
X
X
Urine pregnancy test
Xc
Xc
Ocular discomfort scale
X
X
X
X
X
Best corrected visual acuity
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
Bulbar conjunctival injection 
evaluation
X
X
X
X
X
Ocular conjunctival discharge 
evaluation
X
X
X
X
X
AdenoPlus® test
Xd
Conjunctival swab for bacterial 
culturee
X
Xf
Xf
Xf
X
Conjunctival swab to test for HSV, 
and chlamydia and gonorrheal
X
Non-dilated/dilated fundus 
examinationk
X
X
Randomizationg
X
Dispense investigational producth
X
Instill investigational product
Xh
Xi
Xi
Collect investigational product
X
Xb
Compliance assessment
X
X
X
Xb
Drug accountability
X
Xb
Adverse events
Xj
X
X
X
X
Study completion
X


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Table 1
Schedule of Assessments
Procedure
(All ocular assessments and 
procedures performed bilaterally)
Visit 1
Screeninga and 
Baseline
(Day 1)
-1 Day
Visit 2
(Day 3)
Visit 3
(Day 5)
Visit 4
(Day 8)
Visit 5b
(Day 12)
+1 Day
ET=early termination; 
a Informed consent and confirmation of inclusion/exclusion criteria can be conducted on Day -1; these criteria must 
be reconfirmed on Day 1.
b If investigational product is discontinued, regardless of the reason, all discontinued subjects should proceed to Visit 
5 whenever possible. Subjects who discontinue the study and proceed to Visit 5 should perform all Visit 5 
assessments as well as drug return, compliance, and accountability.
c Women of childbearing potential, prior to enrollment and at exit from the study
d If not previously conducted within 24 hours of Visit 1 (Day 1)
e One swab sample from inferior conjunctival cul-de-sac of each eye will be collected for all bacterial testing.
f Conjunctival swab samples MUST be taken at least 12 hours after the last dose of investigational product at Visits 
2, 3, 4, and ET, if applicable.
g All assessments, randomization, and investigational product instillation on Day 1 must take place with sufficient 
time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses).
h The investigational product bottle should be shaken well prior to use at each dosing. The first dose will be 
administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a day for 7 
days.
i Investigational product instillation should only be performed in-office if it is necessary.
j Monitoring for adverse events will begin after informed consent is obtained.
k If a non-dilated fundus exam is not feasible, a dilated examination should be conducted. For each subject, the exam 
should be conducted the same way (either non-dilated or dilated) at both Visits 1 and 5 (or ET).  
l This sample will be used for baseline HSV testing for all subjects. For subjects <2 months of age, testing for 
chlamydia and gonorrhea detection will also be conducted using the same sample.


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Conjunctivitis affects all populations worldwide of all ages and social strata, irrespective of 
gender. Infectious conjunctivitis (adenoviral and bacterial) represents a serious public health 
issue due to a risk of highly infectious epidemics, lost productivity, significant subject 
discomfort, and, in some cases, permanent visual compromise from long-term, immune-mediated 
sequelae (Capriotti et al., 2010; Ford et al., 1987; Gordon et al., 1993; Nauheim et al., 1990; 
Pelletier et al., 2009). Bacterial conjunctivitis is the second-most common cause of infectious 
conjunctivitis with a viral etiology being the most common cause (Azari and Barney, 2013). 
Bacterial etiology is more common in children, potentially accounting for 50-75% of all 
infectious conjunctivitis cases occurring in children (Azari and Barney, 2013). The condition is 
caused by a wide variety of bacteria, including gram-positive species such as Staphylococcus 
aureus and Streptococcus pneumoniae and gram-negative species such as Haemophilus 
influenzae, Chlamydia trachomatis, and Moraxella catarrhalis (Azari and Barney, 2013; Chen 
and Starr, 2008; CDC, 2010; Dias et al., 2013; Haas et al., 2005; Patel et al., 2007; Rours et al., 
2008). Bacterial conjunctivitis typically lasts for 7 to 10 days, yet, in the absence of adequate 
treatment, it can last for weeks or months.
1.2
Product Background and Clinical Information
SHP640, a novel topical ophthalmic suspension, is currently under development for the treatment 
of infectious conjunctivitis (adenoviral and bacterial).
SHP640 contains 2 active ingredients: povidone-iodine (PVP-I) and dexamethasone. PVP-I is a 
multivalent broad-spectrum local antiseptic with bactericidal and fungicidal properties. The 
effect on vegetative cells of various bacteria and fungi is due to the liberation of free iodine from 
the complex. It is effective against many viruses, protozoa, yeasts, cysts, and spores (Betadine, 
2004). Dexamethasone is a corticosteroid routinely used as a topical ophthalmic suspension for 
the treatment of ocular inflammation. It suppresses the inflammatory response to a variety of 
causes of inflammation (Maxidex, 2007). Both components are currently approved for use in 
other indications (at similar or higher concentrations) and have been shown to be safe and 
efficacious for use on the ocular surface in humans. The combination of PVP-I and 
dexamethasone has been shown to rapidly kill common ocular pathogens, including viruses, 
gram-positive bacteria (including methicillin-resistant Staphylococcus aureus [MRSA]), and 
gram-negative bacteria (Pelletier et al., 2013).
Always refer to the latest version of the SHP640 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy, and safety of SHP640. 


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The clinical presentation of conjunctivitis is often nonspecific, and differential diagnosis of 
different types of conjunctivitis can be challenging (Azari and Barney, 2013; O'Brien et al., 
2009). Diagnostic testing to differentiate the underlying cause of infection is rarely performed in 
a clinical setting; misdiagnosis can occur in up to 50% of cases, which often results in improper 
antibiotic treatment (Visscher et al., 2009). Incorrect treatment can not only increase healthcare 
costs from unnecessary antibiotic prescriptions and repeat office visits, but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or MRSA). In 
addition, there is also a risk of overuse and misuse of antibiotics, which are ineffective in the 
treatment of viral infections (Statham et al., 2008). An unmet medical need therefore exists for a 
safe and efficacious treatment that addresses both bacterial and adenoviral conjunctivitis, 2 of the 
leading causes of acute infectious conjunctivitis.
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, 
with dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious 
and inflammatory components of adenoviral and bacterial conjunctivitis.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical 
resolution (defined as absence of bulbar conjunctival injection and ocular conjunctival discharge) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye 
at Visit 3 (Day 5).
2.2.2
Key Secondary Objective
The key secondary objective is to evaluate the efficacy of SHP640 based on bacterial eradication 
(defined as absence of all bacterial species present at or above pathological threshold at baseline) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye 
at Visit 3 (Day 5).
2.2.3
Secondary Objectives
The secondary objectives are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints: 

Clinical resolution of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12)

Bacterial eradication at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) 

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12)


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
The global clinical score (sum of bulbar conjunctival injection and ocular conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 5), 4 (Day 8), and 5 (Day 12) 

Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) 

Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither 
injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12) 

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12) 

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the 
treatment of subjects with bacterial conjunctivitis

Use of rescue medication
2.2.4
Exploratory Objectives
The exploratory objectives of this study are as follows: 

To evaluate ocular discomfort due to conjunctivitis symptoms in subjects receiving SHP640 
compared to PVP-I and placebo at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
SHP640-303 is a global, multicenter, randomized, double-masked, parallel-group, placebo-
controlled study designed to demonstrate the safety and efficacy of SHP640 ophthalmic 
suspension compared to placebo in treating bacterial conjunctivitis. In addition, an exploratory 
arm of PVP-I 0.6% ophthalmic solution will be included.
Approximately 721 subjects will be randomized into the study at Visit 1 (Day 1). Randomization 
will be stratified by age to maintain the randomization ratio among subjects <6 years, 6 to <18 
years, and subjects ≥18 years. Subjects will be randomized 3:1:3 to receive either SHP640, PVP-
I, or placebo within each stratum. 
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced randomization will be used in this study to 
maintain the randomization ratio within each stratum. 


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Once screening and baseline assessments are complete and subjects are confirmed eligible to 
enroll in the study, subjects will be randomized, and investigational product will be administered 
on the same day (Day 1). The first dose will be administered by site staff on Day 1, and 
thereafter subjects will administer 1 drop in each eye 4 times a day (QID) for 7 days. Additional 
visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). All follow-up 
procedures will be conducted at Visit 5 (Day 12). The study will last up to 13 days. 
Figure 1 provides the study design.
Figure 1
SHP640-303 Study Design
PVP-I=povidone iodine
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 13 days. The 
study will be completed in approximately 1.5 years. 
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit (Visit 5) 
or contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
The study will be conducted in approximately 90 sites across North America, South America, 
Asia/Pacific, Europe, Middle East, and Africa.
4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed. If a subject is younger 
than the legal age of consent (per local laws), the subject’s parent(s), guardian, or legally 
authorized representative will provide written informed consent; the subject will provide verbal 
or written assent as appropriate.


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4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions (by the parent(s), guardian, or legally authorized representative, if applicable).
2. Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), 
guardian, or legally authorized representative(s) informed consent (and assent, if applicable) 
to participate in the study.
3. Subjects of any age at Visit 1 (Note: subjects <3 months of age at Visit 1 must have been 
full-term, ie, ≥37 weeks gestational age at birth).
4. Have a negative AdenoPlus® test in both eyes within 24 hours of Visit 1 or at Visit 1.
5. Have a clinical diagnosis of suspected bacterial conjunctivitis in at least 1 eye confirmed by 
the presence of the following minimal clinical signs and symptoms in that same eye:

Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤3 days prior to 
Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection 
Scale

Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
6. Be willing to discontinue contact lens wear for the duration of the study.
7. Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as 
measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will 
be assessed by an age appropriate method in accordance with the AAP Policy Statement for 
Visual System Assessment in Infants, Children, and Young Adults by Pediatricians 
(Donahue and Baker, 2016; American Academy of Pediatrics, 2016). The policy statement 
recommends formal vision screening can begin at 3 years of age. VA measurements for 
children under the age of 3 will be done at the discretion of the investigator. If not done, child 
should be able to fixate on and follow a moving object, except subjects <2 months of age 
who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion 
of investigator.
8. Male, or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. Current or recurrent disease that could affect the action, absorption, or disposition of the 
investigational product, or clinical or laboratory assessments, per investigator’s discretion.


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2. Current or relevant history of physical or psychiatric illness, any medical disorder that may
make the subject unlikely to fully complete the study, or any condition that presents undue 
risk from the investigational product or procedures.
3. Have known or suspected intolerance or hypersensitivity to the investigational product, 
closely related compounds, or any of the stated ingredients. 
4. Prior enrollment in a FST-100 or SHP640 clinical study.
5. Subjects who are employees, or immediate family members of employees (who are directly 
related to study conduct), at the investigational site.
6. Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned 
for the period of the study.
7. Have a preplanned overnight hospitalization during the period of the study.
8. Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, 
iritis, ulcerative keratitis, chronic blepharoconjunctivitis), other than bacterial conjunctivitis.
9. Have active or a history of ocular herpes.
10. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with 
the diagnosis of ocular allergy, toxic conjunctivitis, or non-bacterial ocular infection (eg, 
viral, fungal, acanthamoebal, other parasitic). 
11. Neonates or infants (ie. subjects less than 12 months of age) who have suspected or 
confirmed (based on the result of any test conducted prior to screening) conjunctivitis of 
gonococcal, chlamydial, herpetic or chemical origin.
12. Neonates or infants (ie. subjects less than 12 months of age) whose birth mothers had any 
sexually transmitted disease within 1 month of delivery or any history of genital herpes.
13. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
14. Presence of any significant ophthalmic condition (eg, Retinopathy of Prematurity, congenital 
cataract, congenital glaucoma) or other congenital disorder with ophthalmic involvement that 
could affect study variables.
15. Be a known intraocular pressure (IOP) steroid responder, have a known history of glaucoma, 
be a glaucoma suspect, or have a known history of an elevated IOP >21 mmHg.
16. Have any known clinically significant optic nerve defects. 
17. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to 
previous corneal trauma or dry eye syndrome; presence of corneal epithelial defect or any 
significant corneal opacity at Visit 1.
18. Presence of significant, active condition in the posterior segment that requires invasive 
treatment (eg, intravitreal treatment with vascular endothelial growth factor inhibitors or 
corticosteroids) and may progress during the study participation period. 
19. Have used any topical ocular or systemic antibiotics within ≤7 days of enrollment. 
20. Have used any topical ocular non-steroidal anti-inflammatory drugs within ≤1 day of 
enrollment.


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21. Have used any topical ophthalmic steroids in the last ≤14 days.
22. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 
days prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no 
anticipated change in dose for the duration of the study. Topical dermal steroids are allowed 
except in the periocular area.
23. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
24. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all 
topical ophthalmic products for the duration of the study. Use of hot or cold compresses is 
also not permitted during the study.  
25. Have any significant ocular disease (eg, Sjogren’s syndrome) or any uncontrolled systemic 
disease or debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted 
diseases/infections, diabetes, or cystic fibrosis) that may affect the study parameters, per 
investigator’s discretion.
26. Any known history of immunodeficiency disorder or known active conditions predisposing 
to immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of  
active hepatitis A (anti-hepatitis A virus immunoglobulin M), or organ or bone marrow 
transplantation.
27. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study.
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception throughout the study period. If hormonal contraceptives are used, they should be 
administered according to the package insert. Females of childbearing potential who are not 
currently sexually active must agree to use acceptable contraception, as defined below, if they 
become sexually active during the period of the study.
Female children and adolescent subjects should be either:

Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine pregnancy test at Visit 1. Females of 
childbearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Adult female subjects should be either:


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
Postmenopausal (12 consecutive months of spontaneous amenorrhea and ≥age 51 years)

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of childbearing potential with a negative urine pregnancy test at Visit 1 and prior to 
randomization. Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use acceptable methods of contraception. 
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Intrauterine hormone-releasing systems plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam) 

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the screening visit (Visit 1), plus condoms. 
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). 
Rescue treatment with a licensed antibiotic according to the local standard of care should be 
provided to subjects if, in the judgment of the investigator, there is no clinical improvement or 
worsening of their condition to an extent that it would be in the best interest of the subject to be 
treated with an alternate therapy for safety reasons. In such instances, the investigational product 
should be discontinued, Visit 5 evaluations be performed at the time of subject discontinuation 
after which rescue treatment will be started. 
The investigator is encouraged to discuss withdrawal of a subject from investigational product 
with the medical monitor if necessary.
If investigational product is discontinued for any reason other than a positive HSV baseline test, 
the evaluations listed for Visit 5 are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified follow-up (proceed 
to Visit 5). Comments (spontaneous or elicited) or complaints made by the subject must be 
recorded in the source documents. The reason for termination and the date of stopping 
investigational product must be recorded in the case report form (CRF) and source documents.
Subjects who test positive for ocular HSV at baseline in either eye should have their 
investigational product discontinued, and should receive alternate appropriate treatment as 
needed based on the Investigator’s judgment. These subjects should be followed for the 


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remaining duration of study at regularly scheduled visits, and all safety related assessments 
should be completed (AEs, BCVA, slit lamp biomicroscopy at all visits; fundus exam at Visit 5).
If a subject <2 months of age has a positive CT-NG test for any one of the two Visit 1 samples, 
the subject will be discontinued from the study and started with alternate standard of care therapy 
per the Investigator’s clinical judgment.
Subject numbers for subjects who discontinue will not be reused.
4.4.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF. 
Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol deviation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Physician decision

Study terminated by sponsor

Withdrawal by parent(s)/guardian/legally authorized representative (if applicable)

Other (If “Other” is selected, the investigator must specify on the CRF.)
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment received within 30 days prior to the screening visit (Visit 1; or 
pharmacokinetic equivalent of 5 half-lives, whichever is longer) and through the final study 
contact (including protocol-defined follow-up period) must be recorded on the appropriate CRF 
page.


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5.1
Prior Treatment
Prior treatment includes all treatment received within 30 days prior to the screening visit 
(Visit 1) (or pharmacokinetic equivalent of 5 half-lives, whichever is longer). Prior treatment 
information must be recorded on the appropriate CRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment other than the investigational production taken 
between the dates of the first dose of investigational product and the end of Visit 5 (the end of 
study visit), inclusive. Concomitant treatment information must be recorded on the appropriate 
CRF page.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
Medications not indicated as prohibited are permitted, including treatments for general 
non-excluded medical conditions.
In the event of an emergency, any needed medications may be prescribed without prior approval, 
but the medical monitor must be notified of the use of any prohibited medications immediately 
thereafter.
5.2.2
Prohibited Treatment
Table 2 details the washout period for common prior treatments that are excluded medications 
for this study. 
Table 2
Common Excluded Treatments and Associated Washout Periods
Minimum Time Prior to First Dose
Notes
Treatment
30 days 
14 days
7 days
1 day
2 hours
Topical ocular NSAIDs
X
Topical ocular or systemic antibiotics
X
Topical ophthalmic steroids
X
Systemic corticosteroid agents
X
Stable use of inhaled or nasal 
corticosteroids
X
Allowed ≥30 days if 
no anticipated dose 
changes during the 
study
Noncorticosteroid immunosuppressive 
agents
X


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Table 2
Common Excluded Treatments and Associated Washout Periods
Topical ophthalmic solutions, 
including tear substitutes, and OTC 
preparations (ie, lid scrubs)
X
Must be able to 
discontinue use for 
the duration of the 
study
NSAID=non-steroidal anti-inflammatory drug; OTC=over-the-counter
Treatments not listed in Table 2 are considered permitted. 
6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
Three test products will be used in the clinical development program. The drug product is 
SHP640 (0.1% dexamethasone and 0.6% PVP-I) ophthalmic suspension, the comparator is 0.6% 
PVP-I ophthalmic solution, and the placebo product is placebo ophthalmic solution. Each of 
these test products are manufactured aseptically and filled in sterile plastic ophthalmic bottles. 
The placebo contains 2 additional ingredients relative to the others: benzalkonium chloride, 
United States Pharmacopeia (USP), EP, used as a preservative, and caramel color, National 
Formulary (NF), included to match the dark brown color of the PVP-I active ingredient. 
Additional information on the 3 test products is provided in the current SHP640 investigator’s 
brochure.
6.1.1
Masking the Treatment Assignment
The packaging, appearance, and labeling of the test products will match. Colorant will be added 
to the placebo to match the appearance of SHP640 and the PVP-I ophthalmic solution. Treatment 
assignment will be determined by the randomization schedule.
6.1.2
Commercially Obtained Investigational Product
Not Applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive response technology (IRT) vendor will be used for this study to manage packaged 
investigational medicinal product (IMP) supply, IMP shipments, receipt of IMP at clinical sites, 
randomization of IMP to subjects, expiry tracking, IMP returns, accountability of IMP, and 
emergency unmasking. 
6.2.2
Allocation of Subjects to Treatment 
This is a double-masked, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule.


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Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment is 
automatically assigned by the IRT.
Randomization will be stratified by age to maintain the randomization ratio among subjects <6 
years, 6 to <18 years, and subjects ≥18 years. Subjects will be randomly assigned to receive 
SHP640, PVP-I 0.6%, or placebo based on a 3:1:3 ratio (SHP640:PVP-I:placebo) within the 
randomization strata.
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced randomization (Pocock and Simon, 1975) will 
be used in this study to maintain the randomization ratio within each stratum. The randomization 
will be done centrally. 
6.2.3
Dosing
Subjects will be instructed to instill 1 drop of investigational product in each eye QID (with a 
minimum of 2 hours between doses) for 7 days.
Prior to administration of the first dose, the bottle should be removed from refrigeration and 
allowed to come to room temperature. The bottle will not be refrigerated before subsequent 
administrations. Storage requirements are discussed in Section 6.3.3.
The investigational product bottle should be shaken well prior to use at each dosing.
In-office dosing will only be performed at the first visit, and additionally if necessary. 
6.2.4
Unmasking the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor as soon as possible after the 
unmasking occurs. 
In the event that the treatment assignment is broken, the date and person who broke the code will 
be recorded by the IRT, and the reason for breaking will be recorded on the CRF. Upon breaking 
the mask, the subject will be withdrawn from the study but should complete Visit 5 (the end of 
study visit) to be followed up for safety purposes. Any code breaks that occur must be reported 
to the sponsor’s medical monitor. 


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6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and carton identification are applied to the investigational 
product(s) container. 
All investigational product is labeled with a minimum of the following: protocol number, 
investigational product identification number, dosage form, directions for use, storage 
conditions, expiry date (if applicable), batch number and/or packaging reference number, the 
statements “For clinical trial use only” and/or “CAUTION: New Drug – Limited by Federal (or 
US) Law to Investigational Use,” and the sponsor’s name and address. Any additional labeling 
requirements for participating countries and/or controlled substances will also be included on the 
label, if necessary.
Space is allocated on the label so that the site representative can record the date dispensed, the 
subject’s initials (as permitted based on local laws), and the unique subject number.
Additional labels may, on a case-by-case basis, be applied to the investigational product in order 
to satisfy local or institutional requirements but must not: 

Contradict the clinical study label. 

Obscure the clinical study label. 

Identify the study subject by name. 
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers.
The investigational product bottle will be labeled and then placed into a 1x-labeled carton. This 
carton will then be secured with a tamper seal.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigational product must be stored at the site in a secure, refrigerated area (2-8ºC) 
accessible only to the investigator and his/her designees. The investigational product will be 
administered only to subjects enrolled in the clinical study, in accordance with the conditions 
specified in this protocol.
Undispensed investigational product should be stored under refrigeration at 2-8ºC.


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Dispensed investigational product should be stored at room temperature below 30ºC. 
Investigational product should be protected from freezing and exposure to strong light.
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier and initials as permitted based on local laws 
on the investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system or a mechanical recording device such as a calibrated chart recorder or by 
manual means, such that both minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required. Such a device (ie, certified min/max 
thermometer) would require manual resetting upon each recording. The sponsor must be notified 
immediately upon discovery of any excursion from the established range. Temperature 
excursions will require site investigation as to cause and remediation. The sponsor will determine 
the ultimate impact of excursions on the investigational product and will provide supportive 
documentation as necessary. Under no circumstances should the product be dispensed to subjects 
until the impact has been determined and the product is deemed appropriate for use by the 
sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
Not Applicable.
6.4
Drug Accountability  
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content, and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.


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The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All dispensed 
investigational product will be documented on the CRFs and/or other investigational product 
record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the mask of the study is not compromised.
With the written agreement of the sponsor, at the end of the study all unused stock and 
empty/used investigational product packaging may be destroyed at the site or a local facility. In 
this case, destruction records identifying what was destroyed as well as when and how must be 
obtained with copies provided to the sponsor. Destruction of investigational products must be in 
accordance with local, state, and national laws.
If a site is not approved by the sponsor to destroy the investigational product, all used and unused 
stock is to be sent to a nominated contractor on behalf of the sponsor. Investigational products 
being returned to the sponsor’s designated contractors must be counted and verified by clinical 
site personnel and the sponsor (or designated contractor research organization [CRO]). Validated 
electronic return systems (ie, IRT) may not require a shipment form. Returned investigational 
products must be packed in a tamper-evident manner to ensure product integrity. Contact the 
sponsor for authorization to return any investigational product prior to shipment. Shipment of all 
returned investigational product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Subjects must be instructed to bring their investigational product and empty/used investigational 
product packaging to every visit. The pharmacist/nominated person will record details on the 
drug accountability form.
Subject compliance will be verified verbally during study visits. In cases of non-compliance, the
investigator should determine if the medical monitor must be contacted for consultation. 


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7.
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Assessments (see Table 1) and must be referred to in conjunction with the 
instructions provided in this section. Procedures or assessments that are not completed or are 
performed out of order should be captured as protocol deviations.
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject (as per 
local requirements). If a subject is younger than the legal age of consent (per local laws), the 
subject’s parent(s), guardian, or legally authorized representative will provide written informed 
consent; the subject will provide verbal or written assent as appropriate. There must be 
documentation of consent/assent (as per local requirements) indicating that the subject is aware 
of the investigational nature of the study and the required procedures and restrictions, prior to 
performing any study-related procedures. 
Where applicable, all procedures will be performed in both eyes.
7.1.1
Visit 1 (Day 1)
Screening and baseline/randomization will occur at Visit 1. Visit 1 assessments, beginning with 
informed consent, will be performed as outlined in Table 1.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product. Subjects cannot be rescreened once they have been designated as a 
screen failure.
A urine pregnancy test will be completed for all females of childbearing potential. The results 
will be read by site personnel and recorded in the source documents.
All AEs occurring after signature of informed consent must be recorded in the source documents 
and CRF. 
Prior to randomization, the procedures should be performed in the following order (in both eyes, 
as appropriate):

Informed consent (and assent, if applicable)

Inclusion/exclusion criteria

Medical history

Demographics

Concomitant medications

Urine pregnancy test (for women of childbearing potential)


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
Ocular discomfort scale

BCVA

Slit lamp biomicroscopy

Bulbar conjunctival injection evaluation

Ocular conjunctival discharge evaluation

AdenoPlus® test (if not previously conducted within 24 hours of Visit 1)
If any findings during screening exams do not meet the inclusion/exclusion criteria, the subject is 
not eligible to be randomized. 
Eligible subjects must have a positive response in at least one eye. A positive response is defined 
as meeting ALL of the following criteria in the same eye:

Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤3 days prior to 
Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection 
Scale

Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
Study eye will not be determined at Visit 1. All ophthalmic assessments will be conducted on 
both eyes. Selection of study eye for analyses will be according to the criteria outlined in 
Section 9.8.1.
The procedures should be performed in the following order:

Conjunctival bacterial culture collection (1 swab per eye). An additional swab from each eye 
will be collected in subjects <2 months of age for testing the presence of chlamydia and 
gonorrhea 

Non-dilated/dilated fundus examination

Randomization

Dispense and instill investigational product in both eyes by the designated site staff 
investigational product administrator. The investigational product bottle should be shaken 
well prior to use at each dosing.
All assessments, randomization, and investigational product instillation on Day 1 must take place 
with sufficient time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses).


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7.1.2
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8)
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8) assessments will be performed as outlined in Table 1
and as described in the Study Operations Manual. Assessments should be performed in 
descending order as listed.
Subject compliance will be verified verbally during study visits. In cases of non-compliance, the 
investigator should determine if the medical monitor must be contacted for consultation. 
Subjects should not instill investigational product within 12 hours of scheduled study visits. To 
ensure this, subjects should be reminded to not dose the morning of Visits 2, 3, and 4. 
Investigational product instillation should only be performed in-office if it is necessary and 
should be done once all other assessments are completed. Subjects who instill investigational 
product less than 12 hours before study visits will be recorded as protocol deviations.
7.1.3
Visit 5 (End of Study or Early Termination)
Safety follow-up will be conducted at Visit 5 (the end-of-study visit). Visit 5 (Day 12) 
assessments will be performed as outlined in Table 1. Assessments should be performed in 
descending order as listed.
Subjects who discontinue the study and proceed to Visit 5 for early termination should have 
investigational product collected, a compliance assessment, and drug accountability assessed at 
their final visit.
All AEs and serious AEs (SAEs) that are not resolved at the time of Visit 5 or early termination 
will be followed to closure (see Section 8.1).
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
7.2.1.1
Demographics
Demographic information will be collected at Visit 1. Date of birth (where permitted), age, sex, 
race, and ethnicity will be recorded.
7.2.1.2
Medication and Medical History
MEDICATION HISTORY
Refer to Section 5 for full details on collection of prior treatment.
The investigator will categorize treatments as ocular (specified as left eye, right eye, or both 
eyes) or non-ocular-based on the indication for use. Prior treatment information must be recorded 
on the appropriate CRF page. 


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MEDICAL HISTORY
The site must record all clinically or medically relevant information regardless of how much time 
has elapsed since the date of any diagnosis. Medical history will be classified as ocular (specified 
as left eye, right eye or both eyes)   or non-ocular by the investigator. History should include but 
is not limited to: 

History of ocular diseases/conditions 

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, and any other non-ocular diseases/underlying conditions within 
the past year prior to the screening visit (Visit 1)
7.2.1.3
AdenoPlus Test
The AdenoPlus test will be performed at Visit 1 (unless results are available from a test 
performed within 24 hours of Visit 1) as outlined in Table 1. A negative result in both eyes is 
required for enrollment in this study.
The AdenoPlus test is an in-office test that allows for the detection of adenoviral antigens 
directly from human eye fluid. A small tear sample is transferred onto the AdenoPlus test, which 
confirms the presence of adenovirus and the viral form of conjunctivitis. 
Please refer to the Study Operations Manual for a detailed description of the AdenoPlus Test and 
administration.
7.2.2
Efficacy
7.2.2.1
Clinical Resolution
Clinical resolution of bacterial conjunctivitis is defined as the absence (score=0) of bulbar 
conjunctival injection and ocular conjunctival discharge in the study eye. Bulbar conjunctival 
injection will be assessed based on a 0-4 scale that uses pictures from the Validated Bulbar 
Redness (VBR) Scale, and ocular conjunctival discharge will be assessed based on a 0-3 scale. 
Details of the bulbar conjunctival injection and ocular conjunctival discharge scales are located 
in the Study Operations Manual.
7.2.2.2
Bacterial Eradication
Bacterial eradication for an eye is defined as absence of all bacterial species present at or above 
pathological threshold at baseline in that eye. 
Pathological threshold for individual bacterial species will be based on colony-forming unit 
(CFU)/mL threshold levels established by Cagle and modified by Leibowitz for different ocular 
bacterial species found in the specimens collected from each subject (Leibowitz, 1991). Bacterial 
species will be determined by Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass 
Spectrometry, using their protein patterns.
Additional details are located in the Study Operations Manual. 


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7.2.3
Safety
Safety assessments will be performed in both eyes.
7.2.3.1
Best Corrected Visual Acuity
The BCVA will be performed prior to slit lamp examination during the study as outlined in 
Table 1. 
The complete instructions for performing the BCVA are in the Study Operations Manual. 
Changes in visual acuity (VA) will be assessed for clinical significance. Clinically significant 
changes should be recorded in the source and on the electronic CRF (eCRF) as an AE.
For subjects who are too young to use an ETDRS chart, use an age-appropriate measurement 
method in accordance with the AAP Policy Statement for Visual System Assessment in Infants, 
Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American Academy of 
Pediatrics, 2016; located in the Study Operations Manual) The policy statement recommends 
formal vision screening can begin at 3 years of age. VA measurements for children under the age 
of 3 will be done at the discretion of the investigator. If not done, child should be able to fixate 
on and follow a moving object. This is not a requirement in subjects <2 months of age since the 
ability does not develop until about 2 months of age. However, if an infant <2 months of age is 
able to fix and follow, it should be recorded. The enrollment of subjects <2 months of age will be 
based on subject qualifying all other eligibility criteria and Investigator discretion.
7.2.3.2
Slit Lamp Biomicroscopy
Slit lamp biomicroscopy (or handheld slit lamp) will be performed during the study as outlined 
in Table 1. Magnification of the slit lamp will be consistent with standard clinical practice. The 
subject will be seated.
Observations will be graded as normal or abnormal. Abnormal findings will be described, and 
clinically significant abnormalities should be recorded in the source and on the eCRF (in medical 
history at screening; any changes from the screening visit may be recorded as AEs by the 
investigator). Please note the investigator may use his/her discretion to determine whether not 
clinically significant (NCS) and disease progression should be considered AEs). The following 
will be examined at each visit: 

Lids 

Conjunctiva 

Cornea

Anterior chamber

Iris

Lens


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For infants and young children, if the above exams cannot be performed with a slit lamp or a 
hand held slit lamp, an external examination is to be conducted in accordance with the AAP’s 
Policy Statement for Visual System Assessment in Infants, Children, and Young Adults by 
Pediatricians (Donahue and Baker, 2016; American Academy of Pediatrics, 2016; located in the 
Study Operations Manual). The examination of lens in these subjects should be conducted at 
Visits 1 and 5 (or ET visit) and graded based on the external examination and red reflex exam 
(Section 7.2.3.3). All other structures listed above will be examined and graded at all visits based 
on the external examination. Observations will be graded as normal or abnormal. Abnormal 
findings will be described.
7.2.3.3
Non-dilated/Dilated Fundus Examination
Fundus examination must be conducted after BCVA, slit lamp biomicroscopy, and conjunctival 
swab for bacterial culture has been collected. 
A non-dilated fundus examination will be performed in all subjects with the exception of infants 
and uncooperative small children during the study as outlined in Table 1.
Observations will be graded as normal or abnormal. Abnormal findings will be described.
The following will be examined:

Vitreous

Optic Nerve

Macula
Clinically significant changes should be recorded in the source and on the eCRF as an AE.
If a non-dilated fundus exam is attempted and is not feasible, a dilated fundus exam should be 
conducted. The test should be conducted the same way (either dilated or non-dilated) at both 
Visits 1 and 5 (or ET).
For infants and small children in whom a fundus examination cannot be done, a red reflex exam 
will be conducted in accordance with the AAP Policy Statement for Visual System Assessment 
in Infants, Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American 
Academy of Pediatrics, 2016; located in the Study Operations Manual). Observations will be 
graded as normal or abnormal. Abnormal findings will be described. The red reflex should be 
normal (present and symmetrical for both eyes) at the screening/baseline visit.
7.2.3.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.) Any AE that occurs after the first dose of 
investigational product instillation will be considered a treatment-emergent AE (TEAE).


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Adverse events may also be determined by the investigator during study examinations as 
mentioned in previous sections.
7.2.3.5
Microbiology Laboratory Evaluations
All laboratory assays will be performed according to the laboratory’s normal procedures. 
All bioanalytical assays for the study will be validated following Food and Drug Administration 
(FDA)/International Conference on Harmonisation (ICH) guidelines, based on the method’s 
intended use. The lab will only receive sample identification numbers and collection dates, and 
the lab results will then be transferred to the central lab for data analysis. The lab will not receive 
any information on subject treatment assignment.
One swab sample from inferior conjunctival cul-de-sac of each eye will be collected at all study 
visits for all bacterial testing. An additional sample will be collected from each eye at Visit 1 for 
qualitative detection of herpes simplex virus (HSV). This sample will also be used for PCR 
qualitative detection of chlamydia and gonorrhea in subjects <2 months of age. 
Bacterial eradication as well as antibiotic sensitivity will be determined based on bacterial 
cultures using standard microbiological laboratory procedures. 
7.2.3.6
Pregnancy Test 
A urine pregnancy test is performed on all females of childbearing potential at Visits 1 and 5, or 
if pregnancy is suspected. Urine pregnancy test kits will be provided by the sponsor and read on 
site by qualified site personnel.
7.2.3.7
Health-related Quality of Life Assessments
Ocular discomfort associated with conjunctivitis symptoms will be assessed through the ocular 
discomfort scale (ODS). The ODS is composed of 3 items: pain, itching, and foreign body 
sensation. All items will be evaluated using a 0-10 scale. A separate scale will be administered 
for children younger than 8 years of age. Please see the Study operations manual for a detailed 
description of this assessment.
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, and Recording of Adverse 
Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 


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study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event, including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:


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Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.


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Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine -hCG 
test or ultrasound result will determine the pregnancy onset date.
8.1.6
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category:

Abuse – Persistent or sporadic intentional intake of investigational product when used for a
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: This includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol.)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a pre-specified total daily dose of 4 drops per eye of the product. 

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reported as a medication 
error.


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The administration and/or use of an expired investigational product should be reported as a 
medication error.
In cases of overdose, the investigator should determine if the medical monitor must be contacted 
for consultation.
All investigational product provided to pediatric subjects should be administered or supervised 
by the parent(s)/guardian/legally authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure, which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO/Shire medical monitor 
within 24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see 
Section 8.1.6) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the CRO/Shire medical monitor using the details specified in the emergency 
contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires in-subject hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 


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hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency
room or at home, blood dyscrasias or convulsions that do not result in in subject 
hospitalization, or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject provides 
written informed consent (and assent, if applicable) until the defined follow-up period stated in 
Section 7.1.3 and must be reported to the Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 


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changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and/or the clinical CRO is responsible for notifying the relevant regulatory 
authorities and Institutional Review Boards (IRBs)/ethics committees (ECs) of related, 
unexpected SAEs.
In addition, the sponsor and/or the clinical CRO is responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the SHP640 
program. 
The investigator is responsible for notifying the local IRB, local EC, or relevant local regulatory 
authority of all SAEs that occur at his or her site as required.
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigator’s authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the CRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRF Completion Guidelines. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unmask the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 


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handled in such a way that, prior to unmasking, any data that may unmask study team personnel 
will be presented as masked information or otherwise will not be made available. If applicable, 
unmasked data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be addressed.
In addition to a final SAP for the final analysis, a separate SAP for the interim analysis will be 
finalized prior to unmasking and performing the interim analysis. The SAP for the final analysis 
will be finalized prior to unmasking of the study to preserve the integrity of the statistical 
analysis and study conclusions. 
All final statistical analyses will be performed after the database is locked and unmasked.
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513) Version 
9.2 or higher. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
An unmasked interim analysis (IA) will be performed after ~50% subjects exit the trial in the 
modified intent-to-treat (mITT) population (ie, n=252 in mITT), with data to be analyzed entered 
into the database, queried, and discrepancies resolved. The purpose of the IA will be to assess the 
adequacy of the initial sample size estimation by evaluating conditional power for the primary 
comparison of SHP640 versus placebo on clinical resolution in the treatment of subjects with 
bacterial conjunctivitis in the study eye at Visit 3 (Day 5). There is no intention to stop early for 
efficacy or futility based on the results from the IA. 
The IA will be performed by an external unmasked independent statistician and/or unmasked 
programmers based on a prespecified interim SAP. The interim SAP will explicitly describe how 
the conditional power is to be calculated and the precise rules for altering the sample size 
depending on the potential results. The interim SAP will be finalized prior to IA. The interim 
statistical report including the results will be distributed only to a limited group of people who 
are not involved in the conduct of the trial. All sponsor, CRO, and site staff involved in the 
conduct of the trial must remain masked throughout the trial. Recommendation from the IA to 
increase the sample size may require an amendment to the study protocol. No adjustment of type 
I error rate is needed because the sole purpose of the planned IA is to adjust the sample size by 
using the conditional power approach, and the sample size will be changed only under certain 
conditions (Mehta and Pocock, 2011).


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9.6
Sample Size Calculation and Power Considerations
The sample size was estimated for the primary comparison of SHP640 versus placebo on clinical 
resolution in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 
(Day 5) using nQuery Advisor 7.0. Subjects will be randomized 3:1:3 to receive either SHP640, 
PVP-I, or placebo within each age stratum. 
A sample size of 504 subjects (216 subjects in each of the SHP640 and placebo groups, 72 in
PVP-I group) will ensure ~90% power to compare the SHP640 and placebo treatment groups 
assuming 61% and 45% subjects with clinical resolution, respectively, using Fisher’s Exact test 
at 2-sided 5% level of significance. All efficacy analyses will be based on the mITT with post-
baseline last observation carried forward for the subjects with missing clinical resolution status 
as Visit 3 (Day 5).
An exploratory PVP-I arm (ie, 72 subjects in mITT and approximately 103 randomized subjects) 
will be included in the trial to provide parameter estimates on PVP-I treatment effect to inform 
future studies. No formal hypothesis testing will be conducted on the PVP-I arm. 
To ensure 504 subjects in the mITT population, approximately 721 subjects will be randomized 
in this study (approximately 309 subjects in each of SHP640 and placebo groups; approximately 
103 subjects in PVP-I group).
9.7
Study Population
The Safety Population will include all subjects who receive at least 1 dose of investigational 
product.
The Intent-to-Treat (ITT) Population will include all randomized subjects. 
The mITT Population consists of a subset of the ITT population who receive at least 1 dose of 
investigational product and have a positive bacterial culture (presence of 1 or more bacterial 
species at or above pathological threshold) at baseline in the study eye.
9.8
Efficacy Analyses
The analyses on primary, key secondary, secondary, and exploratory efficacy endpoints will be 
performed on the mITT population (unless specified otherwise) and will be presented by 
treatment group. 
Additional sensitivity analyses may be conducted in the ITT population.
For both efficacy and safety analyses, baseline is defined as the assessments taken prior to 
treatment at Visit 1 (Day 1).


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9.8.1
Study Eye Designation
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a 
score of at least 1 for both ocular conjunctival discharge and bulbar conjunctival redness at 
baseline (baseline is defined as the assessments taken prior to treatment at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive bacterial culture (presence of 1 
or more bacterial species at or above pathological threshold) at baseline or both eyes eligible 
and both with a non-positive bacterial culture (absence of any bacterial species at or above 
pathological threshold) at baseline, the study eye will be the eye with the highest global 
clinical score (sum of bulbar conjunctival injection and ocular conjunctival discharge) at 
baseline. If both eyes have the same global clinical score at baseline, then the study eye will 
be the right eye. 

For subjects with both eyes eligible with a positive bacterial culture in 1 eye at baseline, the 
baseline bacterial culture positive eye will be the study eye. 

For subjects with only 1 eligible eye, the eligible eye will be the study eye irrespective of its 
baseline bacterial culture result. 
The study eye designation is summarized in the table below:
Eligible Eye(s)
Bacterial Culture Results
Study Eye
Both eyes
Both eyes positive
Highest global clinical score at Visit 1 (Day 1)
(or right eye if scores are the same)
Both eyes
Both eyes negative
Highest global clinical score at Visit 1 (Day 1)
(or right eye if scores are the same)
Both eyes
One eye positive
The bacterial culture positive eye at Visit 1 (Day 1) 
One eye
Positive or negative for either eye
The eligible eye 
9.8.2
Primary Efficacy Endpoint
The primary efficacy endpoint is clinical resolution status (defined as absence [ie, a score of 0] 
of bulbar conjunctival injection and ocular conjunctival discharge) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo.
All efficacy analyses will be performed on the mITT population and presented by treatment 
groups. There is a single primary comparison for the single primary endpoint. Therefore, no 
adjustment of multiplicity is needed for the hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 5) will be 
compared between the SHP640 and placebo group. The comparison will be based on the 
proportion of subjects with clinical resolution in the study eye at Visit 3 (Day 5) using Fisher’s 
Exact test at 2-sided 0.05 significance level. 
If subjects have missing clinical resolution status at Visit 3 (Day 5), then the last post-baseline 
observation will be carried forward for the determination of clinical resolution of the study eye. 


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The null hypothesis to be tested is that there is no difference in proportion of subjects with 
clinical resolution in the study eye between SHP640 ophthalmic solution and placebo with the 
alternative of the non-zero difference in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 2-sided Fisher’s Exact 
test at 5% level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical 
method(s) including other methods of imputation of missing data. Sensitivity analyses may be 
conducted in the ITT population in addition to the mITT. In addition, descriptive statistics will 
be generated for the primary efficacy endpoint by treatment within the overall pediatric 
population (ie, birth to 18 years) and within each pediatric age stratum (<6 years and 6 to <18 
years) in mITT. A detailed plan for primary analysis including additional sensitivity analyses 
will be described in the SAP.
9.8.3
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoint is bacterial eradication status (defined as absence of all 
bacterial species present at or above pathological threshold at baseline) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo.
All efficacy analyses will be performed on the mITT population and presented by treatment 
groups. In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary 
hypotheses will be tested sequentially. Each hypothesis will be tested using Fisher’s Exact test at 
2-sided 5.0% level with null hypothesis of no difference in the proportion of subjects for the 
endpoint between the 2 treatment groups. 
First, the primary efficacy endpoint will be tested. Only if the null hypothesis for the primary 
efficacy endpoint is rejected at 5.0% level, then the key secondary efficacy endpoint of bacterial 
eradication will be tested to compare the proportion of subjects with bacterial eradication 
between the SHP640 and placebo treatment group. If subjects have missing bacterial eradication 
status at Visit 3 (Day 5), then the last post-baseline observation will be carried forward for the 
determination of bacterial eradication of the study eye. 
Sensitivity analyses will also be done on key secondary efficacy endpoints using similar methods 
as described above. In addition, descriptive statistics will be generated for the key secondary 
efficacy endpoint by treatment within the overall pediatric population (ie, birth to 18 years) and 
within each pediatric age stratum (<6 years and 6 to <18 years) in the mITT. Details on the 
analyses will be described in the SAP.
9.8.4
Secondary Efficacy Endpoints
All secondary efficacy analyses will be performed on the mITT population and presented by 
treatment group. No hypothesis testing is planned for the secondary efficacy endpoints. All 
secondary efficacy endpoint will be summarized by treatment groups using descriptive statistics 
at each assessment visit. Continuous endpoints will be summarized by number of subjects (n), 
mean, median, standard deviation, minimum, maximum, and confidence intervals (CIs). Binary 


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endpoints will be summarized by number of subjects (n), frequencies, proportions, and CIs. Time 
to event endpoint will be summarized by Kaplan-Meier survival estimates.
Secondary efficacy endpoints are defined as follows:

Clinical resolution status of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12) in the study eye

Bacterial eradication status (defined as absence of all bacterial species present at or above 
pathological threshold at baseline) as assessed by bacterial culture at Visits 2 (Day 3), 4 (Day 
8), and 5 (Day 12) in the study eye

Absolute and change from baseline of the individual clinical signs score (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12) in the study eye

The global clinical score (defined as the sum of bulbar conjunctival injection and ocular 
conjunctival discharge) and change from baseline in the global clinical score at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with 
neither injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), 
and 5 (Day 12) in the study eye

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), 
and 5 (Day 12) in the study eye

Use of rescue medication
9.8.5
Exploratory Efficacy Endpoints
The ocular discomfort endpoints will be evaluated by absolute and change from baseline of 
ocular discomfort scores (or by the binary ocular discomfort endpoint for children younger than 
8 years of age) due to conjunctivitis symptoms at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12) (mITT population and ITT population). 
No hypothesis testing is planned for the exploratory efficacy endpoint. Exploratory endpoints 
will be summarized using methods similar to secondary endpoints.
9.9
Safety Analyses
Safety data will be presented for the safety population by treatment group and overall.
Safety data collected at baseline prior to treatment (Visit 1/Day 1) will be used as the baseline 
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Adverse events, including those suggestive of any local tolerability issues, will be coded using 
the Medical Dictionary for Regulatory Activities. The number of subjects and percentage with a 
TEAE as well as the number of TEAEs will be calculated overall, by system organ class, by 
preferred term, and by treatment group. Treatment-emergent adverse events will be further 
summarized by severity and relationship to investigational product. Adverse events related to 
investigational product, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized and listed.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or a 
non-ocular AE.
The following safety endpoints will be descriptively summarized by treatment group at each 
applicable visit:

BCVA

Slit lamp biomicroscopy

Lid 

Conjunctiva 

Cornea 

Anterior chamber 

Iris

Lens 

Non-dilated/dilated fundus examination

Vitreous 

Optic nerve 

Macula 

Urine pregnancy testing (for females of childbearing potential)
9.10
Other Analyses
No other analyses are planned in this study.
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, European Union 
(EU) Directive 2001/20/EC and its updates, and local ethical and legal requirements.
In case of substantial amendment, approval from the Competent Regulatory Authority will be 
sought before implementation. 


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The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC and its updates, as well as all applicable national and local laws and 
regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.


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10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study that has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC and its updates, and applicable regulatory requirements and 
guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
The coordinating principal investigator will be assigned and selected based on the extent of their 
involvement in the study and experience in the therapeutic area.
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.


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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs to ensure accurate and timely information is provided at all 
phases during the study may be done by the sponsor, applicable CRO, investigator, or, for 
multicenter studies, coordinating principal investigator according to national provisions and will 
be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data. All corrections to the eCRF must indicate the reason for 
change. If corrections are made after the review and signature by the investigator, he or she must 
be made aware of the change, and his or her awareness must be documented by re-signing the 
eCRF.   
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include but are not limited to the 
subject’s medical file, scales, ODS, and documented results of AdenoPlus test results.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) will check the CRF 
entries against the source documents. The consent form includes a statement by which the
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 


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regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
European Medicines Agency (EMA), United Kingdom Medicines and Healthcare products 
Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation, or honoraria; any proprietary interest in investigational product; and any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to 
the objectives, potential benefits and risk, inconveniences, and subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.


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Within the source documents, site personnel should document instruction of and understanding 
by the parent(s)/guardian/legally authorized representative/caregiver of the safe, responsible 
storage and administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form and assent form, 
where applicable, that was reviewed by the IRB/EC and received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the CRO.


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The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP640; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, other information (eg, initials and 
date of birth if the local law permits) may also be collected and used to assist the sponsor to 
verify the accuracy of the data (eg, to confirm that laboratory results have been assigned to the 
correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to 
and used in other countries that may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on


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medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.


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11.
REFERENCES
American Academy of Pediatrics 2016. Visual system assessment in infants, children, and young 
adults by pediatricians. Pediatrics, 137, 28-30.
Azari, A. A. & Barney, N. P. 2013. Conjunctivitis: a systematic review of diagnosis and 
treatment. Jama, 310, 1721-9.
Betadine 2004. Betadine Prescribing Information.
Capriotti, J. A., Stewart, K. P. & Pelletier, J. 2010. The unique challenges of viral conjunctivitis -
Its similarities to bacterial infection belie key differences that impact clinical care 
[Online]. Ophthalmology Management. Available: 
http://www.ophthalmologymanagement.com/articleviewer.aspx?articleid=104651.
CDC. 2010. Conjunctivitis (pink eye) [Online]. Centers for Disease Control and Prevention. 
Available: http://www.cdc.gov/conjunctivitis/clinical.html.
Chen, C. J. & Starr, C. E. 2008. Epidemiology of gram-negative conjunctivitis in neonatal 
intensive care unit patients. Am J Ophthalmol, 145, 966-970.e2.
Dias, C., Gonçalves, M. & João, A. 2013. Epidemiological study of hospital-acquired bacterial 
conjunctivitis in a level III neonatal unit. Sci World J, 1-5.
Donahue, S. P. & Baker, C. N. 2016. Procedures for the Evaluation of the Visual System by 
Pediatricians. Pediatrics, 137.
Ford, E., Nelson, K. E. & Warren, D. 1987. Epidemiology of epidemic keratoconjunctivitis. 
Epidemiol Rev, 9, 244-61.
Gordon, Y. J., Gordon, R. Y., Romanowski, E. & Araullo-Cruz, T. P. 1993. Prolonged recovery 
of desiccated adenoviral serotypes 5, 8, and 19 from plastic and metal surfaces in vitro. 
Ophthalmology, 100, 1835-9; discussion 1839-40.
Haas, J., Larson, E., Ross, B., See, B. & Saiman, L. 2005. Epidemiology and diagnosis of 
hospital-acquired conjunctivitis among neonatal intensive care unit patients. Pediatr 
Infect Dis J, 24, 586-589.
Leibowitz HM. Antibacterial effectiveness of ciprofloxacin 0.3% ophthalmic solution in the 
treatment of bacterial conjunctivitis. Am J Ophthalmol. 1991 Oct;112(4 Suppl):29S-33S.
Maxidex 2007. Maxidex Prescribing Information.
Mehta, C. R. & Pocock, S. J. 2011. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Statistics in medicine, 30, 3267-84.
Nauheim, R. C., Romanowski, E. G., Araullo-Cruz, T., Kowalski, R. P., Turgeon, P. W., Stopak, 
S. S. & Gordon, Y. J. 1990. Prolonged recoverability of desiccated adenovirus type 19 
from various surfaces. Ophthalmology, 97, 1450-3.
O'Brien, T. P., Jeng, B. H., McDonald, M. & Raizman, M. B. 2009. Acute conjunctivitis: truth 
and misconceptions. Curr Med Res Opin, 25, 1953-61.
Patel, P. B., Diaz, M. C. G., Bennett, J. E. & Attia, M. W. 2007. Clinical features of bacterial 
conjunctivitis in children. Clin Investigations, 1-5.
Pelletier, J. S., Stewart, K., Trattler, W., Ritterband, D. C., Braverman, S., Samson, C. M., Liang, 
B. & Capriotti, J. A. 2009. A combination povidone-iodine 0.4%/dexamethasone 0.1% 
ophthalmic suspension in the treatment of adenoviral conjunctivitis. Adv Ther, 26, 776-
83.
Pelletier, M. R., Casella, L. G., Jones, J. W., Adams, M. D., Zurawski, D. V., Hazlett, K. R., Doi, 
Y. & Ernst, R. K. 2013. Unique structural modifications are present in the 


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lipopolysaccharide from colistin-resistant strains of Acinetobacter baumannii. Antimicrob 
Agents Chemother, 57, 4831-40.
Pocock, S. J. & Simon, R. 1975. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 31, 103-15.
Rours, I. G. I. J. G., Hammerschlag, M. R., Ott, A., De Faber, T. J. T. H. N., Verbrugh, H. A., de 
Groot, R. & Verkooyen, R. P. 2008. Chlamydia trachomatis as a cause of neonatal 
conjunctivitis in Dutch infants. Pediatrics, 121, e321.
Statham, M. O., Sharma, A. & Pane, A. R. 2008. Misdiagnosis of acute eye diseases by primary 
health care providers: incidence and implications. Med J Aust, 189, 402-4.
Visscher, K. L., Hutnik, C. M. & Thomas, M. 2009. Evidence-based treatment of acute infective 
conjunctivitis: Breaking the cycle of antibiotic prescribing. Can Fam Physician, 55,
1071-5.


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12.
APPENDICES




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APPENDIX 2
SCALES AND ASSESSMENTS
All scales assessments referenced in the protocol, including procedural instructions for the 
investigator, are in the Study Operations Manual and the Laboratory Manual (provided upon 
request).

Prot_004.pdf: 
PROTOCOL SHP640-303
TITLE:
A Phase 3, Multi-center, Randomized, Double-Masked Study to 
Evaluate the Clinical Efficacy and Safety of SHP640 (PVP-Iodine 0.6% 
and Dexamethasone 0.1%) Ophthalmic Suspension Compared to 
Placebo in the Treatment of Bacterial Conjunctivitis
DRUG:
SHP640
IND:
75,723
EUDRACT NO:
2016-003361-25
SPONSOR:
Shire
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 27 September 2016
Amendment 1: 28 November 2016
Amendment 2: 15 February 2017
Amendment 3: 13 December 2017
Amendment 4: 31 July 2018
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire




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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to the Shire Global Pharmacovigilance and Risk Management 
Department. Applicable fax numbers and e-mail address can be found on the form (sent under 
separate cover). A copy of this form must also be sent to the contract research organization 
(CRO)/Shire medical monitor by fax or e-mail using the details below.
Fax: 
Email: 
For protocol- or safety-related issues in the United States (US) and North American region, 
the investigator must contact the Shire medical monitor:
 MBBS, DPM, MS
Primary telephone number: 
Fax: 
Alternate number: 
For protocol- or safety-related issues in regions other than North America, the investigator 
must contact the Quintiles 24/7 Emergency Contact center:
Primary telephone number: 
Alternate number:




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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA), 


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS........................................................................................................11
STUDY SYNOPSIS ......................................................................................................................12
1.
BACKGROUND INFORMATION.......................................................................................21
1.1
Indication and Current Treatment Options...............................................................21
1.2
Product Background and Clinical Information ........................................................21
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................22
2.1
Rationale for the Study.............................................................................................22
2.2
Study Objectives ......................................................................................................22
2.2.1
Primary Objective..................................................................................................22
2.2.2
Key Secondary Objective ......................................................................................22
2.2.3
Secondary Objectives.............................................................................................22
2.2.4
Exploratory Objectives ..........................................................................................23
3.
STUDY DESIGN ...................................................................................................................24
3.1
Study Design and Flow Chart ..................................................................................24
3.2
Duration and Study Completion Definition .............................................................24
3.3
Sites and Regions .....................................................................................................25
4.
STUDY POPULATION.........................................................................................................26
4.1
Inclusion Criteria......................................................................................................26
4.2
Exclusion Criteria.....................................................................................................27
4.3
Reproductive Potential .............................................................................................28
4.3.1
Female Contraception............................................................................................28
4.4
Discontinuation of Subjects .....................................................................................29
4.4.1
Reasons for Discontinuation..................................................................................30
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................30
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
5.1
Prior Treatment ........................................................................................................32
5.2
Concomitant Treatment............................................................................................32
5.2.1
Permitted Treatment...............................................................................................32
5.2.2
Prohibited Treatment .............................................................................................32


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6.
INVESTIGATIONAL PRODUCT ........................................................................................34
6.1
Identity of Investigational Product...........................................................................34
6.1.1
Masking the Treatment Assignment ......................................................................34
6.1.2
Commercially Obtained Investigational Product...................................................34
6.2
Administration of Investigational Product(s)...........................................................34
6.2.1
Interactive Response Technology for Investigational Product Management ........34
6.2.2
Allocation of Subjects to Treatment ......................................................................34
6.2.3
Dosing....................................................................................................................35
6.2.4
Unmasking the Treatment Assignment..................................................................35
6.3
Labeling, Packaging, Storage, and Handling ...........................................................35
6.3.1
Labeling .................................................................................................................35
6.3.2
Packaging...............................................................................................................36
6.3.3
Storage ...................................................................................................................36
6.3.4
Special Handling....................................................................................................37
6.4
Drug Accountability.................................................................................................37
6.5
Subject Compliance..................................................................................................38
7.
STUDY PROCEDURES........................................................................................................39
7.1
Study Schedule.........................................................................................................39
7.1.1
Visit 1 (Day 1) .......................................................................................................39
7.1.2
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8) ............................................................41
7.1.3
Visit 5 (End of Study or Early Termination) .........................................................41
7.1.4
Additional Care of Subjects after the Study ..........................................................41
7.2
Study Evaluations and Procedures ...........................................................................41
7.2.1
Demographic and Other Baseline Characteristics .................................................41
7.2.1.1
Demographics.........................................................................................41
7.2.1.2
Medication and Medical History............................................................41
7.2.1.3
AdenoPlus Test ......................................................................................42
7.2.2
Efficacy..................................................................................................................42
7.2.2.1
Clinical Resolution.................................................................................42
7.2.2.2
Bacterial Eradication..............................................................................42
7.2.3
Safety .....................................................................................................................43
7.2.3.1
Best Corrected Visual Acuity.................................................................43
7.2.3.2
Slit Lamp Biomicroscopy.......................................................................43
7.2.3.3
Non-dilated/Dilated Fundus Examination..............................................44
7.2.3.4
Adverse Event Collection.......................................................................44
7.2.3.5
Microbiology Laboratory Evaluations ...................................................45
7.2.3.6
Pregnancy Test .......................................................................................45
7.2.3.7
Health-related Quality of Life Assessments...........................................45


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................46
8.1
Definition of Adverse Events, Period of Observation, and Recording of 
Adverse Events.........................................................................................................46
8.1.1
Severity Categorization..........................................................................................46
8.1.2
Relationship Categorization...................................................................................47
8.1.3
Outcome Categorization ........................................................................................47
8.1.4
Symptoms of the Disease Under Study .................................................................47
8.1.5
Pregnancy...............................................................................................................48
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................48
8.2
Serious Adverse Event Procedures ..........................................................................49
8.2.1
Reference Safety Information................................................................................49
8.2.2
Reporting Procedures.............................................................................................49
8.2.3
Serious Adverse Event Definition .........................................................................50
8.2.4
Serious Adverse Event Collection Time Frame.....................................................50
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................50
8.2.6
Fatal Outcome........................................................................................................51
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................51
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................52
9.1
Data Collection.........................................................................................................52
9.2
Clinical Data Management.......................................................................................52
9.3
Data Handling Considerations..................................................................................52
9.4
Statistical Analysis Process......................................................................................52
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......53
9.6
Sample Size Calculation and Power Considerations................................................53
9.7
Study Population ......................................................................................................54
9.8
Efficacy Analyses.....................................................................................................54
9.8.1
Study Eye Designation...........................................................................................54
9.8.2
Primary Efficacy Endpoint ....................................................................................55
9.8.3
Key Secondary Efficacy Endpoints .......................................................................56
9.8.4
Secondary Efficacy Endpoints...............................................................................56
9.8.5
Exploratory Efficacy Endpoints.............................................................................57
9.9
Safety Analyses........................................................................................................57
9.10
Other Analyses .........................................................................................................58
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................59
10.1
Sponsor’s Responsibilities .......................................................................................59
10.1.1 Good Clinical Practice Compliance.......................................................................59
10.1.2 Indemnity/Liability and Insurance.........................................................................59


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10.1.3 Public Posting of Study Information......................................................................59
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................60
10.1.5 Study Suspension, Termination, and Completion..................................................60
10.2
Investigator’s Responsibilities .................................................................................60
10.2.1 Good Clinical Practice Compliance.......................................................................60
10.2.2 Protocol Adherence and Investigator Agreement..................................................61
10.2.3 Documentation and Retention of Records.............................................................61
10.2.3.1
Case Report Forms.................................................................................61
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................61
10.2.3.3
Audit/Inspection.....................................................................................62
10.2.3.4
Financial Disclosure...............................................................................62
10.3
Ethical Considerations..............................................................................................62
10.3.1 Informed Consent...................................................................................................62
10.3.2 Institutional Review Board or Ethics Committee..................................................63
10.4
Privacy and Confidentiality......................................................................................64
10.5
Study Results/Publication Policy .............................................................................64
11. REFERENCES .......................................................................................................................66
12. APPENDICES ........................................................................................................................68
Appendix 1
Protocol History .....................................................................................69
Appendix 2
Scales and Assessments .........................................................................70


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LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................19
Table 2
Common Excluded Treatments and Associated Washout Periods................33
LIST OF FIGURES
Figure 1
SHP640-303 Study Design............................................................................24


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LIST OF ABBREVIATIONS
AAP
American Academy of Pediatrics
AE
adverse event
BCVA
best corrected visual acuity
CFU
colony-forming unit
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
EC
ethics committee
eCRF
electronic case report form
EMA
European Medicines Agency
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
HSV
Herpes Simplex Virus
IA
interim analysis
ICH
International Conference on Harmonisation
IMP
investigational medicinal product
IOP
intraocular pressure
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
mITT
modified intent-to-treat
MRSA
methicillin-resistant Staphylococcus aureus
NCS
not clinically significant
NF
National Formulary
ODS
ocular discomfort scale
PVP-I
povidone-iodine
QID
4 times a day
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment-emergent adverse event
US
United States
USP
United States Pharmacopeia
VA
visual acuity
VBR
Validated Bulbar Redness


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31 Jul 2018
STUDY SYNOPSIS
Protocol number: SHP640-303
Drug: SHP640
Title of the study: A Phase 3, Multi-center, Randomized, Double-Masked Study to Evaluate the Clinical Efficacy 
and Safety of SHP640 (PVP-Iodine 0.6% and Dexamethasone 0.1%) Ophthalmic Suspension Compared to Placebo 
in the Treatment of Bacterial Conjunctivitis
Number of subjects (total and for each treatment arm):
Total subjects: Approximately 854
SHP640 treatment arm: Approximately 366
Povidone-iodine (PVP-I) treatment arm: Approximately 122
Placebo treatment arm: Approximately 366
Investigator(s): multicenter study
Site(s) and Region(s): 
The study will be conducted in approximately 175 sites across North America, South America, Asia/Pacific, Europe, 
the Middle East and Africa.
Study period (planned):
December 2016 to November 2018
Clinical phase:
3
Objectives:
Primary:
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical resolution (defined as 
absence of bulbar conjunctival injection and ocular conjunctival discharge) compared with placebo in the treatment 
of subjects with bacterial conjunctivitis in the study eye at Visit 3 (Day 5). 
Secondary:
The key secondary objective of this study is to evaluate the efficacy of SHP640 based on bacterial eradication 
(defined as absence of all bacterial species present at or above pathological threshold at baseline) compared with 
placebo in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 (Day 5).
Secondary objectives of this study are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints:

Clinical resolution of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12)

Bacterial eradication at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12)

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival injection and ocular 
conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

The global clinical score (sum of bulbar conjunctival injection and ocular conjunctival discharge) and change 
from baseline in the global clinical score at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12)

Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither injection nor
discharge having a score of 2 at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the treatment of subjects 
with bacterial conjunctivitis

Use of rescue medication


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Rationale:
The clinical presentation of conjunctivitis is often nonspecific, and differential diagnosis of different types of 
conjunctivitis can be challenging (Azari and Barney 2013; O’Brien et al. 2009). Diagnostic testing to differentiate 
the underlying cause of infection is rarely performed in a clinical setting; misdiagnosis can occur in up to 50% of 
cases, which often results in improper antibiotic treatment (Visscher et al. 2009). Incorrect treatment can not only 
increase healthcare costs from unnecessary antibiotic prescriptions and repeat office visits but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or methicillin-resistant Staphylococcus 
aureus). In addition, there is also a risk of overuse and misuse of antibiotics, which are ineffective in the treatment 
of viral infections (Statham et al. 2008). An unmet medical need therefore exists for a safe and efficacious treatment 
that addresses both bacterial and adenoviral conjunctivitis, 2 of the leading causes of acute infectious conjunctivitis. 
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, with 
dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious and inflammatory 
components of adenoviral and bacterial conjunctivitis.
Investigational product, dose, and mode of administration:
The drug product is SHP640 (0.1% dexamethasone and 0.6% PVP-I) ophthalmic suspension.
The comparators are placebo ophthalmic solution and 0.6% PVP-I ophthalmic solution.
Subjects will instill 1 drop of investigational product in each eye 4 times daily (with a minimum of 2 hours between 
doses) for 7 days.
Methodology:
Once screening and baseline assessments are complete and subjects are confirmed eligible to enroll in the study, 
subjects will be randomized, and investigational product will be administered on the same day (Day 1). The first 
dose will be administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a 
day for 7 days. Additional visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). The study 
will last up to 13 days. 
Inclusion and exclusion criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions (by 
the parent(s), guardian, or legally authorized representative, if applicable).
2.
Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), guardian, or 
legally authorized representative(s) informed consent (and assent, if applicable) to participate in the 
study.
3.
Subjects of any age at Visit 1 (Note: subjects <3 months of age at Visit 1 must have been full-term, ie 
≥37 weeks gestational age at birth).
4.
Have a negative AdenoPlus® test in both eyes within 24 hours of Visit 1 or at Visit 1.
5.
Have a clinical diagnosis of suspected bacterial conjunctivitis in at least 1 eye confirmed by the 
presence of the following minimal clinical signs and symptoms in that same eye:
5.1. Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤4 days prior to Visit 1
5.2. Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection Scale
5.3. Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
6.
Be willing to discontinue contact lens wear for the duration of the study.


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7.
Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as measured using 
an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will be assessed by an age 
appropriate method in accordance with the AAP Policy Statement for Visual System Assessment in 
Infants, Children, and Young Adults by Pediatricians (Donahue and Baker 2016; American Academy 
of Pediatrics 2016). The policy statement recommends formal vision screening can begin at 3 years of 
age. VA measurements for children under the age of 3 will be done at the discretion of the investigator. 
If not done, child should be able to fixate on and follow a moving object, except subjects <2 months of 
age who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion of 
the investigator.
8.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of non-childbearing potential.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1.
Current or recurrent disease that could affect the action, absorption, or disposition of the 
investigational product, or clinical or laboratory assessments, per investigator’s discretion.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may make the 
subject unlikely to fully complete the study, or any condition that presents undue risk from the 
investigational product or procedures.
3.
Have known or suspected intolerance or hypersensitivity to the investigational product, closely related 
compounds, or any of the stated ingredients. 
4.
Prior enrollment in a FST-100 or SHP640 clinical study.
5.
Subjects who are employees, or immediate family members of employees (who are directly related to 
study conduct), at the investigational site.
6.
Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned for the 
period of the study.
7.
Have a preplanned overnight hospitalization during the period of the study.
8.
Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, iritis, 
ulcerative keratitis, chronic blepharoconjunctivitis), other than bacterial conjunctivitis.
9.
Have active or a history of ocular herpes.
10. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with the 
diagnosis of non-infectious conjunctivitis (except presumed seasonal/perennial allergic conjunctivitis), 
or non-bacterial ocular infection (eg, viral, fungal, acanthamoebal, or other parasitic). Note: history or 
concomitant presence of presumed seasonal or perennial allergic conjunctivitis signs/symptoms is not 
exclusionary.
11. Neonates or infants (ie, subjects less than 12 months of age) who have suspected or confirmed (based 
on the result of any test conducted prior to screening) conjunctivitis of gonococcal, chlamydial, 
herpetic or chemical origin.
12. Neonates or infants (ie, subjects less than 12 months of age) whose birth mothers had any sexually 
transmitted disease within 1 month of delivery or any history of genital herpes.
13. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
14. Presence of any significant ophthalmic condition (eg, Retinopathy of Prematurity, congenital cataract, 
congenital glaucoma) or other congenital disorder with ophthalmic involvement that could affect study 
variables.
15. Be a known intraocular pressure (IOP) steroid responder, have a known history or current diagnosis of 
glaucoma, or be a glaucoma suspect.


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16. Have any known clinically significant optic nerve defects. 
17. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to previous corneal 
trauma or dry eye syndrome; presence of corneal epithelial defect or any significant corneal opacity at 
Visit 1.
18. Presence of significant, active condition in the posterior segment that requires invasive treatment (eg, 
intravitreal treatment with vascular endothelial growth factor inhibitors or corticosteroids) and may 
progress during the study participation period. 
19. Have used any topical ocular or systemic antibiotics within ≤7 days of enrollment. 
20. Have used any topical ocular non-steroidal anti-inflammatory drugs within ≤1 day of enrollment.
21. Have used any topical ophthalmic steroids in the last ≤14 days.
22. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 days 
prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no anticipated change in 
dose for the duration of the study. Topical dermal steroids are allowed except in the periocular area.
23. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
24. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all topical 
ophthalmic products for the duration of the study. Use of hot or cold compresses is also not permitted 
during the study.
25. Have any significant ocular disease (eg, Sjogren’s syndrome) or any uncontrolled systemic disease or 
debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted diseases/infections, 
diabetes, or cystic fibrosis) that may affect the study parameters, per investigator’s discretion.
26. Any known history of immunodeficiency disorder or known active conditions predisposing to 
immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of active 
hepatitis A (anti-hepatitis A virus immunoglobulin M), or organ or bone marrow transplantation.
27. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study.
Maximum duration of subject involvement in the study:
Subject participation will last up to 13 days.
Screening, randomization, and the first treatment administration will occur at Visit 1 (Day 1). 
Additional visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). 
All follow-up procedures will be conducted at Visit 5 (Day 12).
Endpoints and statistical analysis:
Primary Efficacy Endpoint:
Clinical resolution status (defined as absence of bulbar conjunctival injection and ocular conjunctival discharge) in 
the study eye at Visit 3 (Day 5) between SHP640 and placebo.
Key Secondary Efficacy Endpoints:
Bacterial eradication status (defined as absence of all bacterial species present at or above pathological threshold at 
baseline) in the study eye at Visit 3 (Day 5) between SHP640 and placebo.


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31 Jul 2018
Secondary Efficacy Endpoints:

Clinical resolution status of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) in the study 
eye

Bacterial eradication status (defined as absence of all bacterial species present at or above pathological 
threshold at baseline) as assessed by bacterial culture at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) in the study 
eye 

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival injection and ocular 
conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye 

The global clinical score (defined as the sum of bulbar conjunctival injection and ocular conjunctival discharge) 
and change from baseline in the global clinical score at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in 
the study eye 

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12) in the study eye 

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with neither injection nor 
discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye 

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in 
the study eye 

Use of rescue medication 
Safety Endpoints:

BCVA

Slit lamp biomicroscopy 

Non-dilated/dilated fundus examination

Urine pregnancy testing (for females of childbearing potential)

Adverse events (AEs)
Statistical Methods:
The analyses on primary, key secondary, secondary, and exploratory efficacy endpoints will be performed on the 
modified intent-to-treat (mITT) population (unless specified otherwise) and will be presented by treatment group. 
Additional sensitivity analyses may be conducted on the intent-to-treat (ITT) population. Safety analyses will be 
conducted on the safety population.
For both efficacy and safety analyses, baseline is defined as the assessments taken prior to treatment at Visit 1 
(Day 1).
Analysis Populations:
The safety population will include all subjects who receive at least 1 dose of investigational product.
The ITT population will include all randomized subjects. 
The mITT population consists of a subset of the ITT population who receive at least 1 dose of investigational 
product and have a positive bacterial culture (presence of 1 or more bacterial species at or above pathological 
threshold) at baseline in the study eye.


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Designation of Study Eye:
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a score of at least 1 for 
both ocular conjunctival discharge and bulbar conjunctival redness at baseline (baseline is defined as the 
assessments taken prior to treatment at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive bacterial culture (presence of 1 or more bacterial 
species at or above pathological threshold) at baseline or both eyes eligible and both with a non-positive 
bacterial culture (absence of any bacterial species at or above pathological threshold) at baseline, the study eye 
will be the eye with the highest global clinical score (sum of bulbar conjunctival injection and ocular 
conjunctival discharge) at baseline. If both eyes have the same global clinical score at baseline, then the study 
eye will be the right eye.

For subjects with both eyes eligible with a positive bacterial culture in one eye at baseline, the baseline bacterial 
culture positive eye will be the study eye.

For subjects with only 1 eligible eye, the eligible eye will be the study eye irrespective of its baseline bacterial 
culture status.
Primary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. There is a single primary 
comparison for the single primary endpoint. Therefore, no adjustment of multiplicity is needed for the hypothesis 
testing for the primary objective.
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 5) will be compared between the 
SHP640 and placebo group. The comparison will be based on the proportion of subjects with clinical resolution in 
the study eye at Visit 3 (Day 5) using Fisher’s Exact test at 2-sided 0.0499 significance level.
If subjects have missing clinical resolution status at Visit 3 (Day 5), then the last post-baseline observation will be 
carried forward for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with clinical resolution in the 
study eye between SHP640 ophthalmic Solution and placebo with the alternative of the non-zero difference in the 
proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 2-sided Fisher’s Exact test at 4.99% level 
of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical method(s) including 
methods of imputation of missing data. Sensitivity analyses may be conducted in the ITT in addition to the mITT.
Key Secondary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. The key secondary efficacy 
endpoint of this study is bacterial eradication status in the study eye at Visit 3 (Day 5) between SHP640 and placebo. 
In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary hypotheses will be tested 
sequentially. Each hypothesis will be tested using Fisher’s Exact test at 2-sided 4.99% level with null hypothesis of 
no difference in the proportion of subjects for the endpoint between the 2 treatment groups. 
First, the primary efficacy endpoint will be tested. Only if the null hypothesis for the primary efficacy endpoint is 
rejected at 4.99% level, then the key secondary efficacy endpoint of bacterial eradication will be tested to compare 
the proportion of subjects with bacterial eradication between the SHP640 and placebo treatment group. If subjects 
have missing bacterial eradication at Visit 3 (Day 5), then the last post-baseline observation will be carried forward 
for the determination of bacterial eradication of the study eye. 
Sensitivity analyses will also be done on the key secondary efficacy endpoint using similar methods as described 
above.


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Secondary Efficacy Analyses:
No hypothesis testing is planned for the secondary efficacy endpoints. All secondary efficacy endpoints will be 
summarized by treatment groups using descriptive statistics at each assessment visit. Continuous endpoints will be 
summarized by number of subjects (n), mean, median, standard deviation, minimum, maximum, and confidence 
intervals (CIs). Binary endpoints will be summarized by number of subjects (n), frequencies, proportions, and CIs. 
Time to event endpoint will be summarized by Kaplan-Meier survival estimates.
Safety Analyses:
Safety data will be presented for the safety population by treatment group and overall.
Safety data collected at baseline prior to treatment (Visit 1/Day 1) will be used as the baseline value for safety 
analysis. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The number of subjects and 
percentage with a treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated 
overall, by system organ class, by preferred term, and by treatment group and overall. TEAEs will be further 
summarized by severity and relationship to investigational product. AEs related to investigational product, AEs 
leading to withdrawal, serious AEs, and deaths will be similarly summarized and listed. Any AE that occurs after the 
first dose of investigational product instillation will be considered a TEAE.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or a non-ocular AE.
Slit lamp biomicroscopy, non-dilated/dilated fundus exam, BCVA, and urine pregnancy test (for females of 
childbearing potential) will be descriptively summarized by treatment group and overall at each applicable visit.


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Study Schedule
Table 1
Schedule of Assessments
Procedure
(All ocular assessments and 
procedures performed bilaterally)
Visit 1
Screeninga and 
Baseline
(Day 1)
-1 Day
Visit 2
(Day 3)
+1 Day
Visit 3
(Day 5)
Visit 4
(Day 8)
+1 Day
Visit 5b
(Day 12)
+2 Days
Informed consent/assenta
X
Inclusion/exclusion criteriaa
X
Medical history 
X
Demographics
X
Concomitant medications
X
X
X
X
X
Urine pregnancy test
Xc
Xc
Ocular discomfort scale
X
X
X
X
X
Best corrected visual acuity
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
Bulbar conjunctival injection 
evaluation
X
X
X
X
X
Ocular conjunctival discharge 
evaluation
X
X
X
X
X
AdenoPlus® test
Xd
Conjunctival swab for bacterial 
culturee
X
Xf
Xf
Xf
X
Conjunctival swab to test for HSV, 
and chlamydia and gonorrheal
X
Non-dilated/dilated fundus 
examinationk
X
X
Randomizationg
X
Dispense investigational producth
X
Instill investigational product
Xh
Xi
Xi
Collect investigational product
X
Xb
Compliance assessment
X
X
X
Xb
Drug accountability
X
Xb


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Table 1
Schedule of Assessments
Procedure
(All ocular assessments and 
procedures performed bilaterally)
Visit 1
Screeninga and 
Baseline
(Day 1)
-1 Day
Visit 2
(Day 3)
+1 Day
Visit 3
(Day 5)
Visit 4
(Day 8)
+1 Day
Visit 5b
(Day 12)
+2 Days
Adverse events
Xj
X
X
X
X
Study completion
X
ET=early termination; 
a Informed consent and confirmation of inclusion/exclusion criteria can be conducted on Day -1; these criteria must be 
reconfirmed on Day 1.
b If investigational product is discontinued, regardless of the reason, all discontinued subjects should proceed to Visit 5 whenever 
possible. Subjects who discontinue the study and proceed to Visit 5 should perform all Visit 5 assessments as well as drug return, 
compliance, and accountability.
c Women of childbearing potential, prior to enrollment and at exit from the study
d If not previously conducted within 24 hours of Visit 1 (Day 1)
e One swab sample from inferior conjunctival cul-de-sac of each eye will be collected for all bacterial testing.
f Conjunctival swab samples MUST be taken at least 12 hours after the last dose of investigational product at Visits 2, 3, 4, and 
ET, if applicable.
g All assessments, randomization, and investigational product instillation on Day 1 must take place with sufficient time to allow 
all 4 Day 1 doses (with a minimum of 2 hours between doses).
h The investigational product bottle should be shaken well prior to use at each dosing. The first dose will be administered by site 
staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a day for 7 days.
iInvestigational product instillation should only be performed in-office if it is necessary.
jMonitoring for adverse events will begin after informed consent is obtained.
k If a non-dilated fundus exam is not feasible, a dilated examination should be conducted. For each subject, the exam should be 
conducted the same way (either non-dilated or dilated) at both Visits 1 and 5 (or ET).
l This sample will be used for baseline HSV testing for all subjects. For subjects <2 months of age, testing for chlamydia and 
gonorrhea detection will also be conducted using the same sample.


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Conjunctivitis affects all populations worldwide of all ages and social strata, irrespective of 
gender. Infectious conjunctivitis (adenoviral and bacterial) represents a serious public health 
issue due to a risk of highly infectious epidemics, lost productivity, significant subject 
discomfort, and, in some cases, permanent visual compromise from long-term, immune-mediated 
sequelae (Capriotti et al., 2010; Ford et al., 1987; Gordon et al., 1993; Nauheim et al., 1990; 
Pelletier et al., 2009). Bacterial conjunctivitis is the second-most common cause of infectious 
conjunctivitis with a viral etiology being the most common cause (Azari and Barney, 2013). 
Bacterial etiology is more common in children, potentially accounting for 50-75% of all 
infectious conjunctivitis cases occurring in children (Azari and Barney, 2013). The condition is 
caused by a wide variety of bacteria, including gram-positive species such as Staphylococcus 
aureus and Streptococcus pneumoniae and gram-negative species such as Haemophilus 
influenzae, Chlamydia trachomatis, and Moraxella catarrhalis (Azari and Barney, 2013; Chen 
and Starr, 2008; CDC, 2010; Dias et al., 2013; Haas et al., 2005; Patel et al., 2007; Rours et al., 
2008). Bacterial conjunctivitis typically lasts for 7-10 days, yet, in the absence of adequate 
treatment, it can last for weeks or months.
1.2
Product Background and Clinical Information
SHP640, a novel topical ophthalmic suspension, is currently under development for the treatment 
of infectious conjunctivitis (adenoviral and bacterial).
SHP640 contains 2 active ingredients: povidone-iodine (PVP-I) and dexamethasone. 
Povidone-iodine is a multivalent broad-spectrum local antiseptic with bactericidal and fungicidal 
properties. The effect on vegetative cells of various bacteria and fungi is due to the liberation of 
free iodine from the complex. It is effective against many viruses, protozoa, yeasts, cysts, and 
spores (Betadine, 2004). Dexamethasone is a corticosteroid routinely used as a topical 
ophthalmic suspension for the treatment of ocular inflammation. It suppresses the inflammatory 
response to a variety of causes of inflammation (Maxidex, 2007). Both components are currently 
approved for use in other indications (at similar or higher concentrations) and have been shown 
to be safe and efficacious for use on the ocular surface in humans. The combination of PVP-I and 
dexamethasone has been shown to rapidly kill common ocular pathogens, including viruses, 
gram-positive bacteria (including methicillin-resistant Staphylococcus aureus [MRSA]), and 
gram-negative bacteria (Pelletier et al., 2013).
Always refer to the latest version of the SHP640 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy, and safety of SHP640.


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The clinical presentation of conjunctivitis is often nonspecific, and differential diagnosis of 
different types of conjunctivitis can be challenging (Azari and Barney, 2013; O'Brien et al., 
2009). Diagnostic testing to differentiate the underlying cause of infection is rarely performed in 
a clinical setting; misdiagnosis can occur in up to 50% of cases, which often results in improper 
antibiotic treatment (Visscher et al., 2009). Incorrect treatment can not only increase healthcare 
costs from unnecessary antibiotic prescriptions and repeat office visits, but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or MRSA). In 
addition, there is also a risk of overuse and misuse of antibiotics, which are ineffective in the 
treatment of viral infections (Statham et al., 2008). An unmet medical need therefore exists for a 
safe and efficacious treatment that addresses both bacterial and adenoviral conjunctivitis, 2 of the 
leading causes of acute infectious conjunctivitis.
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, 
with dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious 
and inflammatory components of adenoviral and bacterial conjunctivitis.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical 
resolution (defined as absence of bulbar conjunctival injection and ocular conjunctival discharge) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye 
at Visit 3 (Day 5). 
2.2.2
Key Secondary Objective
The key secondary objective is to evaluate the efficacy of SHP640 based on bacterial eradication 
(defined as absence of all bacterial species present at or above pathological threshold at baseline) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye 
at Visit 3 (Day 5).
2.2.3
Secondary Objectives
The secondary objectives are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints: 

Clinical resolution of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12)

Bacterial eradication at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) 

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12)


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
The global clinical score (sum of bulbar conjunctival injection and ocular conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 
3 (Day 5), 4 (Day 8), and 5 (Day 12) 

Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) 

Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither 
injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12) 

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 
4 (Day 8), and 5 (Day 12) 

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the 
treatment of subjects with bacterial conjunctivitis

Use of rescue medication
2.2.4
Exploratory Objectives
The exploratory objectives of this study are as follows: 

To evaluate ocular discomfort due to conjunctivitis symptoms in subjects receiving SHP640 
compared to PVP-I and placebo at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)


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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
SHP640-303 is a global, multicenter, randomized, double-masked, parallel-group, 
placebo-controlled study designed to demonstrate the safety and efficacy of SHP640 ophthalmic 
suspension compared to placebo in treating bacterial conjunctivitis. In addition, an exploratory 
arm of PVP-I 0.6% ophthalmic solution will be included.
Approximately 854 subjects will be randomized into the study at Visit 1 (Day 1). Randomization 
will be stratified by age to maintain the randomization ratio among subjects <6 years, 6 to 
<18 years, and subjects ≥18 years. Subjects will be randomized 3:1:3 to receive either SHP640, 
PVP-I, or placebo within each stratum. 
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced allocation will be used in this study to 
maintain the randomization ratio within each stratum. 
Once screening and baseline assessments are complete and subjects are confirmed eligible to 
enroll in the study, subjects will be randomized, and investigational product will be administered 
on the same day (Day 1). The first dose will be administered by site staff on Day 1, and 
thereafter subjects will administer 1 drop in each eye 4 times a day (QID) for 7 days. Additional 
visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). All follow-up 
procedures will be conducted at Visit 5 (Day 12). The study will last up to 13 days. 
Figure 1 provides the study design.
Figure 1
SHP640-303 Study Design
PVP-I=povidone iodine
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 13 days. The 
study will be completed in approximately 1.5 years. 


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The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit (Visit 5) 
or contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
The study will be conducted in approximately 175 sites across North America, South America, 
Asia/Pacific, Europe, Middle East, and Africa.


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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed. If a subject is younger 
than the legal age of consent (per local laws), the subject’s parent(s), guardian, or legally 
authorized representative will provide written informed consent; the subject will provide verbal 
or written assent as appropriate.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions (by the parent(s), guardian, or legally authorized representative, if applicable).
2. Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), 
guardian, or legally authorized representative(s) informed consent (and assent, if applicable) 
to participate in the study.
3. Subjects of any age at Visit 1 (Note: subjects <3 months of age at Visit 1 must have been 
full-term, ie, ≥37 weeks gestational age at birth).
4. Have a negative AdenoPlus® test in both eyes within 24 hours of Visit 1 or at Visit 1.
5. Have a clinical diagnosis of suspected bacterial conjunctivitis in at least 1 eye confirmed by 
the presence of the following minimal clinical signs and symptoms in that same eye:

Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤4 days prior to 
Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection 
Scale

Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
6. Be willing to discontinue contact lens wear for the duration of the study.
7. Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as 
measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will 
be assessed by an age appropriate method in accordance with the AAP Policy Statement for 
Visual System Assessment in Infants, Children, and Young Adults by Pediatricians 
(Donahue and Baker, 2016; American Academy of Pediatrics, 2016). The policy statement 
recommends formal vision screening can begin at 3 years of age. VA measurements for 
children under the age of 3 will be done at the discretion of the investigator. If not done, child 
should be able to fixate on and follow a moving object, except subjects <2 months of age 
who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion 
of investigator.
8. Male, or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential.


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4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. Current or recurrent disease that could affect the action, absorption, or disposition of the 
investigational product, or clinical or laboratory assessments, per investigator’s discretion.
2. Current or relevant history of physical or psychiatric illness, any medical disorder that may
make the subject unlikely to fully complete the study, or any condition that presents undue 
risk from the investigational product or procedures.
3. Have known or suspected intolerance or hypersensitivity to the investigational product, 
closely related compounds, or any of the stated ingredients. 
4. Prior enrollment in a FST-100 or SHP640 clinical study.
5. Subjects who are employees, or immediate family members of employees (who are directly 
related to study conduct), at the investigational site.
6. Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned 
for the period of the study.
7. Have a preplanned overnight hospitalization during the period of the study.
8. Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, 
iritis, ulcerative keratitis, chronic blepharoconjunctivitis), other than bacterial conjunctivitis.
9. Have active or a history of ocular herpes.
10. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with 
the diagnosis of non-infectious conjunctivitis (except presumed seasonal/perennial allergic 
conjunctivitis) or non-bacterial ocular infection (eg, viral, fungal, acanthamoebal, or other 
parasitic). Note: history or concomitant presence of presumed seasonal or perennial allergic 
conjunctivitis signs/symptoms is not exclusionary.
11. Neonates or infants (ie, subjects less than 12 months of age) who have suspected or 
confirmed (based on the result of any test conducted prior to screening) conjunctivitis of 
gonococcal, chlamydial, herpetic or chemical origin.
12. Neonates or infants (ie, subjects less than 12 months of age) whose birth mothers had any 
sexually transmitted disease within 1 month of delivery or any history of genital herpes.
13. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
14. Presence of any significant ophthalmic condition (eg, Retinopathy of Prematurity, congenital 
cataract, congenital glaucoma) or other congenital disorder with ophthalmic involvement that 
could affect study variables.
15. Be a known intraocular pressure (IOP) steroid responder, have a known history or current 
diagnosis of glaucoma or be a glaucoma suspect.
16. Have any known clinically significant optic nerve defects. 


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17. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to 
previous corneal trauma or dry eye syndrome; presence of corneal epithelial defect or any 
significant corneal opacity at Visit 1.
18. Presence of significant, active condition in the posterior segment that requires invasive 
treatment (eg, intravitreal treatment with vascular endothelial growth factor inhibitors or 
corticosteroids) and may progress during the study participation period. 
19. Have used any topical ocular or systemic antibiotics within ≤7 days of enrollment. 
20. Have used any topical ocular non-steroidal anti-inflammatory drugs within ≤1 day of 
enrollment.
21. Have used any topical ophthalmic steroids in the last ≤14 days.
22. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated 
≥30 days prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no 
anticipated change in dose for the duration of the study. Topical dermal steroids are allowed 
except in the periocular area.
23. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
24. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all 
topical ophthalmic products for the duration of the study. Use of hot or cold compresses is 
also not permitted during the study.
25. Have any significant ocular disease (eg, Sjogren’s syndrome) or any uncontrolled systemic 
disease or debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted 
diseases/infections, diabetes, or cystic fibrosis) that may affect the study parameters, per 
investigator’s discretion.
26. Any known history of immunodeficiency disorder or known active conditions predisposing 
to immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of
active hepatitis A (anti-hepatitis A virus immunoglobulin M), or organ or bone marrow 
transplantation.
27. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study.
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception throughout the study period. If hormonal contraceptives are used, they should be 
administered according to the package insert. Females of childbearing potential who are not 
currently sexually active must agree to use acceptable contraception, as defined below, if they 
become sexually active during the period of the study.


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Female children and adolescent subjects should be either:

Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine pregnancy test at Visit 1. Females of 
childbearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Adult female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and ≥age 51 years)

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of childbearing potential with a negative urine pregnancy test at Visit 1 and prior to 
randomization. Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use acceptable methods of contraception. 
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Intrauterine hormone-releasing systems plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the screening visit (Visit 1), plus condoms. 
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). 
Rescue treatment with a licensed antibiotic according to the local standard of care should be 
provided to subjects if, in the judgment of the investigator, there is no clinical improvement or 
worsening of their condition to an extent that it would be in the best interest of the subject to be 
treated with an alternate therapy for safety reasons. In such instances, the investigational product 
should be discontinued, Visit 5 evaluations be performed at the time of subject discontinuation 
after which rescue treatment will be started. 
The investigator is encouraged to discuss withdrawal of a subject from investigational product 
with the medical monitor if necessary.
If investigational product is discontinued for any reason other than a positive HSV baseline test, 
the evaluations listed for Visit 5 are to be performed as completely as possible. Whenever 


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possible, all discontinued subjects should also undergo the protocol-specified follow-up (proceed 
to Visit 5). Comments (spontaneous or elicited) or complaints made by the subject must be 
recorded in the source documents. The reason for termination and the date of stopping 
investigational product must be recorded in the case report form (CRF) and source documents.
Subjects who test positive for ocular HSV at baseline in either eye should have their 
investigational product discontinued, and should receive alternate appropriate treatment as 
needed based on the investigator’s judgment. These subjects should be followed for the 
remaining duration of study at regularly scheduled visits, and all safety related assessments 
should be completed (AEs, BCVA, slit lamp biomicroscopy at all visits [fundus exam at Visit 5], 
concomitant medications at all visits, and pregnancy test [if the subject is a female of 
childbearing potential]).
If a subject <2 months of age has a positive CT-NG test for any one of the two Visit 1 samples, 
the subject will be discontinued from the study and started with alternate standard of care therapy 
per the investigator’s clinical judgment.
Subject numbers for subjects who discontinue will not be reused.
4.4.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF. 
Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol deviation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Physician decision

Study terminated by sponsor

Withdrawal by parent(s)/guardian/legally authorized representative (if applicable)

Other (If “Other” is selected, the investigator must specify on the CRF.)
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 


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known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.


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5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment received within 30 days prior to the screening visit (Visit 1; or 
pharmacokinetic equivalent of 5 half-lives, whichever is longer) and through the final study 
contact (including protocol-defined follow-up period) must be recorded on the appropriate CRF 
page.
5.1
Prior Treatment
Prior treatment includes all treatment received within 30 days prior to the screening visit 
(Visit 1) (or pharmacokinetic equivalent of 5 half-lives, whichever is longer). Prior treatment 
information must be recorded on the appropriate CRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment other than the investigational production taken 
between the dates of the first dose of investigational product and the end of Visit 5 (the end of 
study visit), inclusive. Concomitant treatment information must be recorded on the appropriate 
CRF page.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
Medications not indicated as prohibited are permitted, including treatments for general 
non-excluded medical conditions.
In the event of an emergency, any needed medications may be prescribed without prior approval, 
but the medical monitor must be notified of the use of any prohibited medications immediately 
thereafter.
5.2.2
Prohibited Treatment
Table 2 details the washout period for common prior treatments that are excluded medications 
for this study. 


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Table 2
Common Excluded Treatments and Associated Washout Periods
Minimum Time Prior to First Dose
Notes
Treatment
30 days 
14 days
7 days
1 day
2 hours
Topical ocular NSAIDs
X
Topical ocular or systemic antibiotics
X
Topical ophthalmic steroids
X
Systemic corticosteroid agents
X
Stable use of inhaled or nasal 
corticosteroids
X
Allowed ≥30 days if 
no anticipated dose 
changes during the 
study
Noncorticosteroid immunosuppressive 
agents
X
Topical ophthalmic solutions, 
including tear substitutes, and OTC 
preparations (ie, lid scrubs)
X
Must be able to 
discontinue use for 
the duration of the 
study
NSAID=non-steroidal anti-inflammatory drug; OTC=over-the-counter
Treatments not listed in Table 2 are considered permitted. 


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
Three test products will be used in the clinical development program. The drug product is 
SHP640 (0.1% dexamethasone and 0.6% PVP-I) ophthalmic suspension, the comparator is 0.6% 
PVP-I ophthalmic solution, and the placebo product is placebo ophthalmic solution. Each of 
these test products are manufactured aseptically and filled in sterile plastic ophthalmic bottles. 
The placebo contains 2 additional ingredients relative to the others: benzalkonium chloride, 
United States Pharmacopeia (USP), EP, used as a preservative, and caramel color, National 
Formulary (NF), included to match the dark brown color of the PVP-I active ingredient. 
Additional information on the 3 test products is provided in the current SHP640 investigator’s 
brochure.
6.1.1
Masking the Treatment Assignment
The packaging, appearance, and labeling of the test products will match. Colorant will be added 
to the placebo to match the appearance of SHP640 and the PVP-I ophthalmic solution. Treatment 
assignment will be determined by the randomization schedule.
6.1.2
Commercially Obtained Investigational Product
Not Applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive response technology (IRT) vendor will be used for this study to manage packaged 
investigational medicinal product (IMP) supply, IMP shipments, receipt of IMP at clinical sites, 
randomization of IMP to subjects, expiry tracking, IMP returns, accountability of IMP, and 
emergency unmasking. 
6.2.2
Allocation of Subjects to Treatment 
This is a double-masked, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment is 
automatically assigned by the IRT.
Randomization will be stratified by age to maintain the randomization ratio among subjects 
<6 years, 6 to <18 years, and subjects ≥18 years. 


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Subjects will be randomly assigned to receive SHP640, PVP-I 0.6%, or placebo based on a 3:1:3 
ratio (SHP640:PVP-I:placebo) within the randomization strata.
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced allocation (Pocock and Simon, 1975) will be 
used in this study to maintain the randomization ratio within each stratum. The randomization 
will be done centrally. 
6.2.3
Dosing
Subjects will be instructed to instill 1 drop of investigational product in each eye QID (with a 
minimum of 2 hours between doses) for 7 days.
Prior to administration of the first dose, the bottle should be removed from refrigeration and 
allowed to come to room temperature. The bottle will not be refrigerated before subsequent 
administrations. Storage requirements are discussed in Section 6.3.3.
The investigational product bottle should be shaken well prior to use at each dosing.
In-office dosing will only be performed at the first visit, and additionally if necessary. 
6.2.4
Unmasking the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor as soon as possible after the 
unmasking occurs. 
In the event that the treatment assignment is broken, the date and person who broke the code will 
be recorded by the IRT, and the reason for breaking will be recorded on the CRF. Upon breaking 
the mask, the subject will be withdrawn from the study but should complete Visit 5 (the end of 
study visit) to be followed up for safety purposes. Any code breaks that occur must be reported 
to the sponsor’s medical monitor. 
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and carton identification are applied to the investigational 
product(s) container. 
All investigational product is labeled with a minimum of the following: protocol number, 
investigational product identification number, dosage form, directions for use, storage 
conditions, expiry date (if applicable), batch number and/or packaging reference number, the 
statements “For clinical trial use only” and/or “CAUTION: New Drug – Limited by Federal (or 
US) Law to Investigational Use,” and the sponsor’s name and address. 


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Any additional labeling requirements for participating countries and/or controlled substances will 
also be included on the label, if necessary.
Space is allocated on the label so that the site representative can record the date dispensed, the 
subject’s initials (as permitted based on local laws), and the unique subject number.
Additional labels may, on a case-by-case basis, be applied to the investigational product in order 
to satisfy local or institutional requirements but must not: 

Contradict the clinical study label. 

Obscure the clinical study label. 

Identify the study subject by name. 
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers.
The investigational product bottle will be labeled and then placed into a 1x-labeled carton. This 
carton will then be secured with a tamper seal.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigational product must be stored at the site in a secure, refrigerated area (2-8ºC) 
accessible only to the investigator and his/her designees. The investigational product will be 
administered only to subjects enrolled in the clinical study, in accordance with the conditions 
specified in this protocol.
Undispensed investigational product should be stored under refrigeration at 2-8ºC.
Dispensed investigational product should be stored at room temperature below 30ºC. 
Investigational product should be protected from freezing and exposure to strong light.
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier and initials as permitted based on local laws 
on the investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. 


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The investigator is responsible for ensuring that the temperature is monitored throughout the 
duration of the study and that records are maintained; the temperature should be monitored 
continuously by using either an in-house system or a mechanical recording device such as a 
calibrated chart recorder or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording. The sponsor must be notified immediately upon discovery of any excursion from the 
established range. Temperature excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the investigational 
product and will provide supportive documentation as necessary. Under no circumstances should 
the product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
Not Applicable.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content, and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All dispensed 
investigational product will be documented on the CRFs and/or other investigational product 
record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.


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The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the mask of the study is not compromised.
With the written agreement of the sponsor, at the end of the study all unused stock and 
empty/used investigational product packaging may be destroyed at the site or a local facility. In 
this case, destruction records identifying what was destroyed as well as when and how must be 
obtained with copies provided to the sponsor. Destruction of investigational products must be in 
accordance with local, state, and national laws.
If a site is not approved by the sponsor to destroy the investigational product, all used and unused 
stock is to be sent to a nominated contractor on behalf of the sponsor. Investigational products 
being returned to the sponsor’s designated contractors must be counted and verified by clinical 
site personnel and the sponsor (or designated contractor research organization [CRO]). Validated 
electronic return systems (ie, IRT) may not require a shipment form. Returned investigational 
products must be packed in a tamper-evident manner to ensure product integrity. Contact the 
sponsor for authorization to return any investigational product prior to shipment. Shipment of all 
returned investigational product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Subjects must be instructed to bring their investigational product and empty/used investigational 
product packaging to every visit. The pharmacist/nominated person will record details on the 
drug accountability form.
Subject compliance will be verified verbally during study visits. In cases of non-compliance, the 
investigator should determine if the medical monitor must be contacted for consultation. 


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7.
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Assessments (see Table 1) and must be referred to in conjunction with the 
instructions provided in this section. Procedures or assessments that are not completed or are 
performed out of order should be captured as protocol deviations.
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject (as per 
local requirements). If a subject is younger than the legal age of consent (per local laws), the 
subject’s parent(s), guardian, or legally authorized representative will provide written informed 
consent; the subject will provide verbal or written assent as appropriate. There must be 
documentation of consent/assent (as per local requirements) indicating that the subject is aware 
of the investigational nature of the study and the required procedures and restrictions, prior to 
performing any study-related procedures. 
Where applicable, all procedures will be performed in both eyes.
7.1.1
Visit 1 (Day 1)
Screening and baseline/randomization will occur at Visit 1 (Day 1 [-1 day]). Visit 1 assessments, 
beginning with informed consent, will be performed as outlined in Table 1.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product. Subjects cannot be rescreened once they have been designated as a 
screen failure.
A urine pregnancy test will be completed for all females of childbearing potential. The results 
will be read by site personnel and recorded in the source documents.
All AEs occurring after signature of informed consent must be recorded in the source documents 
and CRF. 
Prior to randomization, the procedures should be performed in the following order (in both eyes, 
as appropriate):

Informed consent (and assent, if applicable)

Inclusion/exclusion criteria

Medical history

Demographics

Concomitant medications

Urine pregnancy test (for women of childbearing potential)


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
Ocular discomfort scale

BCVA

Slit lamp biomicroscopy

Bulbar conjunctival injection evaluation

Ocular conjunctival discharge evaluation

AdenoPlus® test (if not previously conducted within 24 hours of Visit 1)
If any findings during screening exams do not meet the inclusion/exclusion criteria, the subject is 
not eligible to be randomized. 
Eligible subjects must have a positive response in at least one eye. A positive response is defined 
as meeting ALL of the following criteria in the same eye:

Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤4 days prior to 
Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection 
Scale

Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
Study eye will not be determined at Visit 1. All ophthalmic assessments will be conducted on 
both eyes. Selection of study eye for analyses will be according to the criteria outlined in 
Section 9.8.1.
The procedures should be performed in the following order:

Conjunctival bacterial culture collection (1 swab per eye). An additional swab from each eye 
will be collected in subjects <2 months of age for testing the presence of chlamydia and 
gonorrhea 

Non-dilated/dilated fundus examination

Randomization

Dispense and instill investigational product in both eyes by the designated site staff 
investigational product administrator. The investigational product bottle should be shaken 
well prior to use at each dosing.
All assessments, randomization, and investigational product instillation on Day 1 must take place 
with sufficient time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses).


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7.1.2
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8)
Visits 2 (Day 3 [+1 day]), 3 (Day 5), and 4 (Day 8 [+1 day]) assessments will be performed as 
outlined in Table 1 and as described in the Study Operations Manual. Assessments should be 
performed in descending order as listed.
Subject compliance will be verified verbally during study visits. In cases of non-compliance, the 
investigator should determine if the medical monitor must be contacted for consultation. 
Subjects should not instill investigational product within 12 hours of scheduled study visits. To 
ensure this, subjects should be reminded to not dose the morning of Visits 2, 3, and 4. 
Investigational product instillation should only be performed in-office if it is necessary and 
should be done once all other assessments are completed. Subjects who instill investigational 
product less than 12 hours before study visits will be recorded as protocol deviations.
7.1.3
Visit 5 (End of Study or Early Termination)
Safety follow-up will be conducted at Visit 5 (the end-of-study visit). Visit 5 (Day 12 [+2 days]) 
assessments will be performed as outlined in Table 1. Assessments should be performed in 
descending order as listed.
Subjects who discontinue the study and proceed to Visit 5 for early termination should have 
investigational product collected, a compliance assessment, and drug accountability assessed at 
their final visit.
All AEs and serious AEs (SAEs) that are not resolved at the time of Visit 5 or early termination 
will be followed to closure (see Section 8.1).
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
7.2.1.1
Demographics
Demographic information will be collected at Visit 1. Date of birth (where permitted), age, sex, 
race, and ethnicity will be recorded.
7.2.1.2
Medication and Medical History
Medication History
Refer to Section 5 for full details on collection of prior treatment.
The investigator will categorize treatments as ocular (specified as left eye, right eye, or both 
eyes) or non-ocular-based on the indication for use. Prior treatment information must be recorded 
on the appropriate CRF page. 


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Medical History
The site must record all clinically or medically relevant information regardless of how much time 
has elapsed since the date of any diagnosis. Medical history will be classified as ocular (specified 
as left eye, right eye or both eyes) or non-ocular by the investigator. History should include but is 
not limited to: 

History of ocular diseases/conditions 

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, and any other non-ocular diseases/underlying conditions within 
the past year prior to the screening visit (Visit 1)
7.2.1.3
AdenoPlus Test
The AdenoPlus test will be performed at Visit 1 (unless results are available from a test 
performed within 24 hours of Visit 1) as outlined in Table 1. A negative result in both eyes is 
required for enrollment in this study.
The AdenoPlus test is an in-office test that allows for the detection of adenoviral antigens 
directly from human eye fluid. A small tear sample is transferred onto the AdenoPlus test, which 
confirms the presence of adenovirus and the viral form of conjunctivitis. 
Please refer to the Study Operations Manual for a detailed description of the AdenoPlus Test and 
administration.
7.2.2
Efficacy
7.2.2.1
Clinical Resolution
Clinical resolution of bacterial conjunctivitis is defined as the absence (score=0) of bulbar 
conjunctival injection and ocular conjunctival discharge in the study eye. Bulbar conjunctival 
injection will be assessed based on a 0-4 scale that uses pictures from the Validated Bulbar 
Redness (VBR) Scale, and ocular conjunctival discharge will be assessed based on a 0-3 scale. 
Details of the bulbar conjunctival injection and ocular conjunctival discharge scales are located 
in the Study Operations Manual.
7.2.2.2
Bacterial Eradication
Bacterial eradication for an eye is defined as absence of all bacterial species present at or above 
pathological threshold at baseline in that eye. 
Pathological threshold for individual bacterial species will be based on colony-forming unit 
(CFU)/mL threshold levels established by Cagle and modified by Leibowitz for different ocular 
bacterial species found in the specimens collected from each subject (Leibowitz, 1991). Bacterial 
species will be determined by Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass 
Spectrometry, using their protein patterns.
Additional details are located in the Study Operations Manual. 


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7.2.3
Safety
Safety assessments will be performed in both eyes.
7.2.3.1
Best Corrected Visual Acuity
The BCVA will be performed prior to slit lamp examination during the study as outlined in 
Table 1. 
The complete instructions for performing the BCVA are in the Study Operations Manual. 
Changes in visual acuity (VA) will be assessed for clinical significance. Clinically significant 
changes should be recorded in the source and on the electronic CRF (eCRF) as an AE.
For subjects who are too young to use an ETDRS chart, use an age-appropriate measurement 
method in accordance with the AAP Policy Statement for Visual System Assessment in Infants, 
Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American Academy of 
Pediatrics, 2016; located in the Study Operations Manual) The policy statement recommends 
formal vision screening can begin at 3 years of age. VA measurements for children under the age 
of 3 will be done at the discretion of the investigator. If not done, child should be able to fixate 
on and follow a moving object. This is not a requirement in subjects <2 months of age since the 
ability does not develop until about 2 months of age. However, if an infant <2 months of age is 
able to fix and follow, it should be recorded. The enrollment of subjects <2 months of age will be 
based on subject qualifying all other eligibility criteria and investigator discretion.
7.2.3.2
Slit Lamp Biomicroscopy
Slit lamp biomicroscopy (or handheld slit lamp) will be performed during the study as outlined 
in Table 1. Magnification of the slit lamp will be consistent with standard clinical practice. The 
subject will be seated.
Observations will be graded as normal or abnormal. Abnormal findings will be described, and 
clinically significant abnormalities should be recorded in the source and on the eCRF (in medical 
history at screening; any changes from the screening visit may be recorded as AEs by the 
investigator). Please note the investigator may use his/her discretion to determine whether not 
clinically significant (NCS) and disease progression should be considered AEs). The following 
will be examined at each visit: 

Lids 

Conjunctiva 

Cornea

Anterior chamber

Iris

Lens


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For infants and young children, if the above exams cannot be performed with a slit lamp or a 
hand held slit lamp, an external examination is to be conducted in accordance with the AAP’s 
Policy Statement for Visual System Assessment in Infants, Children, and Young Adults by 
Pediatricians (Donahue and Baker, 2016; American Academy of Pediatrics, 2016; located in the 
Study Operations Manual). The examination of lens in these subjects should be conducted at 
Visits 1 and 5 (or ET visit) and graded based on the external examination and red reflex exam 
(Section 7.2.3.3). All other structures listed above will be examined and graded at all visits based 
on the external examination. Observations will be graded as normal or abnormal. Abnormal 
findings will be described.
7.2.3.3
Non-dilated/Dilated Fundus Examination
Fundus examination must be conducted after BCVA, slit lamp biomicroscopy, and conjunctival 
swab for bacterial culture has been collected. 
A non-dilated fundus examination will be performed in all subjects with the exception of infants 
and uncooperative small children during the study as outlined in Table 1.
Observations will be graded as normal or abnormal. Abnormal findings will be described.
The following will be examined:

Vitreous

Optic Nerve

Macula
Clinically significant changes should be recorded in the source and on the eCRF as an AE.
If a non-dilated fundus exam is attempted and is not feasible, a dilated fundus exam should be 
conducted. The test should be conducted the same way (either dilated or non-dilated) at both 
Visits 1 and 5 (or ET).
For infants and small children in whom a fundus examination cannot be done, a red reflex exam 
will be conducted in accordance with the AAP Policy Statement for Visual System Assessment 
in Infants, Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American 
Academy of Pediatrics, 2016; located in the Study Operations Manual). Observations will be 
graded as normal or abnormal. Abnormal findings will be described. The red reflex should be 
normal (present and symmetrical for both eyes) at the screening/baseline visit.
7.2.3.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.) Any AE that occurs after the first dose of 
investigational product instillation will be considered a treatment-emergent AE (TEAE).


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Adverse events may also be determined by the investigator during study examinations as 
mentioned in previous sections.
7.2.3.5
Microbiology Laboratory Evaluations
All laboratory assays will be performed according to the laboratory’s normal procedures. 
All bioanalytical assays for the study will be validated following Food and Drug Administration 
(FDA)/International Conference on Harmonisation (ICH) guidelines, based on the method’s 
intended use. The lab will only receive sample identification numbers and collection dates, and 
the lab results will then be transferred to the central lab for data analysis. The lab will not receive 
any information on subject treatment assignment.
One swab sample from inferior conjunctival cul-de-sac of each eye will be collected at all study 
visits for all bacterial testing. An additional sample will be collected from each eye at Visit 1 for 
qualitative detection of herpes simplex virus (HSV). This sample will also be used for PCR 
qualitative detection of chlamydia and gonorrhea in subjects <2 months of age. 
Bacterial eradication as well as antibiotic sensitivity will be determined based on bacterial 
cultures using standard microbiological laboratory procedures. 
7.2.3.6
Pregnancy Test 
A urine pregnancy test is performed on all females of childbearing potential at Visits 1 and 5, or 
if pregnancy is suspected. Urine pregnancy test kits will be provided by the sponsor and read on 
site by qualified site personnel.
7.2.3.7
Health-related Quality of Life Assessments
Ocular discomfort associated with conjunctivitis symptoms will be assessed through the ocular 
discomfort scale (ODS). The ODS is composed of 3 items: pain, itching, and foreign body 
sensation. All items will be evaluated using a 0-10 scale. A separate scale will be administered 
for children younger than 8 years of age. Please see the Study Operations Manual for a detailed 
description of this assessment.


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, and Recording of Adverse 
Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event, including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.


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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.


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8.1.5
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine -hCG 
test or ultrasound result will determine the pregnancy onset date.
8.1.6
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category:

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: This includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol.)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a pre-specified total daily dose of 4 drops per eye of the product. 

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.


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Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reported as a medication 
error.
The administration and/or use of an expired investigational product should be reported as a 
medication error.
In cases of overdose, the investigator should determine if the medical monitor must be contacted 
for consultation.
Please refer to the Study Operations Manual for further details on reporting overdose and 
medication errors. An AE should only be reported if any of these events meets the definition of 
an AE as outlined in Section 8.1.
All investigational product provided to pediatric subjects should be administered or supervised 
by the parent(s)/guardian/legally authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure, which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO/Shire medical monitor 
within 24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see 
Section 8.1.6) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the CRO/Shire medical monitor using the details specified in the emergency
contact information section of the protocol.


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8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires in-subject hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in in subject 
hospitalization, or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject provides 
written informed consent (and assent, if applicable) until the defined follow-up period stated in 
Section 7.1.3 and must be reported to the Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.


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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and/or the clinical CRO is responsible for notifying the relevant regulatory 
authorities and Institutional Review Boards (IRBs)/ethics committees (ECs) of related, 
unexpected SAEs.
In addition, the sponsor and/or the clinical CRO is responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the SHP640 
program. 
The investigator is responsible for notifying the local IRB, local EC, or relevant local regulatory 
authority of all SAEs that occur at his or her site as required.


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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigator’s authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. 
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRF Completion Guidelines. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unmask the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unmasking, any data that may unmask study team personnel 
will be presented as masked information or otherwise will not be made available. If applicable, 
unmasked data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be addressed.
In addition to a final SAP for the final analysis, a separate SAP for the interim analysis will be 
finalized prior to unmasking and performing the interim analysis. The SAP for the final analysis 
will be finalized prior to unmasking of the study to preserve the integrity of the statistical 
analysis and study conclusions. 


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All final statistical analyses will be performed after the database is locked and unmasked.
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513) Version 
9.2 or higher. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
An unmasked interim analysis (IA) will be performed after ~50% subjects exit the trial in the 
modified intent-to-treat (mITT) population, with data to be analyzed entered into the database, 
queried, and discrepancies resolved. The purpose of the IA will be to assess the adequacy of the 
initial sample size estimation by evaluating conditional power for the primary comparison of 
SHP640 versus placebo on clinical resolution in the treatment of subjects with bacterial 
conjunctivitis in the study eye at Visit 3 (Day 5). There is no intention to stop early for efficacy 
or futility based on the results from the IA. 
The IA will be performed by an external unmasked independent statistician and/or unmasked 
programmers based on a prespecified interim SAP. The interim SAP will explicitly describe how 
the conditional power is to be calculated and the precise rules for altering the sample size 
depending on the potential results. The interim SAP will be finalized prior to IA. The interim 
statistical report including the results will be distributed only to a limited group of people who 
are not involved in the conduct of the trial. All sponsor, CRO, and site staff involved in the 
conduct of the trial must remain masked throughout the trial. Recommendation from the IA to 
increase the sample size may require an amendment to the study protocol. There is no inflation
of type I error from this IA because the sole purpose of the planned IA is to adjust the sample 
size by using the conditional power approach, and the sample size will be changed only under 
certain conditions (Mehta and Pocock, 2011). However, for conservativeness, two-sided 0.0001 
alpha will be spent for the proposed IA and a two-sided alpha of 0.0499 will be used for final 
analyses.
9.6
Sample Size Calculation and Power Considerations
The sample size was estimated for the primary comparison of SHP640 versus placebo on clinical 
resolution in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 
(Day 5) using nQuery Advisor 7.0. Subjects will be randomized 3:1:3 to receive either SHP640, 
PVP-I, or placebo within each age stratum. 
A sample size of 504 subjects (216 subjects in each of the SHP640 and placebo groups, 72 in 
PVP-I group) will ensure ~90% power to compare the SHP640 and placebo treatment groups 
assuming 61% and 45% subjects with clinical resolution, respectively, using Fisher’s Exact test 
at 2-sided 5% level of significance. All efficacy analyses will be based on the mITT with 
post-baseline last observation carried forward for the subjects with missing clinical resolution 
status as Visit 3 (Day 5).
An exploratory PVP-I arm (ie, 72 subjects in mITT and approximately 103 randomized subjects) 
will be included in the trial to provide parameter estimates on PVP-I treatment effect to inform 
future studies. No formal hypothesis testing will be conducted on the PVP-I arm. 


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To ensure 504 subjects in the mITT population, approximately 854 subjects will be randomized 
in this study to account for the estimated ~40% reduction from ITT population to mITT 
population (approximately 366 subjects in each of SHP640 and placebo groups; approximately 
122 subjects in PVP-I group).
9.7
Study Population
The Safety Population will include all subjects who receive at least 1 dose of investigational 
product.
The Intent-to-Treat (ITT) Population will include all randomized subjects. 
The mITT Population consists of a subset of the ITT population who receive at least 1 dose of 
investigational product and have a positive bacterial culture (presence of 1 or more bacterial 
species at or above pathological threshold) at baseline in the study eye.
9.8
Efficacy Analyses
The analyses on primary, key secondary, secondary, and exploratory efficacy endpoints will be 
performed on the mITT population (unless specified otherwise) and will be presented by 
treatment group. 
Additional sensitivity analyses may be conducted in the ITT population.
For both efficacy and safety analyses, baseline is defined as the assessments taken prior to 
treatment at Visit 1 (Day 1).
9.8.1
Study Eye Designation
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a 
score of at least 1 for both ocular conjunctival discharge and bulbar conjunctival redness at 
baseline (baseline is defined as the assessments taken prior to treatment at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive bacterial culture (presence of 1 
or more bacterial species at or above pathological threshold) at baseline or both eyes eligible 
and both with a non-positive bacterial culture (absence of any bacterial species at or above 
pathological threshold) at baseline, the study eye will be the eye with the highest global 
clinical score (sum of bulbar conjunctival injection and ocular conjunctival discharge) at 
baseline. If both eyes have the same global clinical score at baseline, then the study eye will 
be the right eye. 

For subjects with both eyes eligible with a positive bacterial culture in 1 eye at baseline, the 
baseline bacterial culture positive eye will be the study eye. 

For subjects with only 1 eligible eye, the eligible eye will be the study eye irrespective of its 
baseline bacterial culture result. 


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The study eye designation is summarized in the table below:
Eligible Eye(s)
Bacterial Culture Results
Study Eye
Both eyes
Both eyes positive
Highest global clinical score at Visit 1 (Day 1)
(or right eye if scores are the same)
Both eyes
Both eyes negative
Highest global clinical score at Visit 1 (Day 1)
(or right eye if scores are the same)
Both eyes
One eye positive
The bacterial culture positive eye at Visit 1 (Day 1) 
One eye
Positive or negative for either eye
The eligible eye 
9.8.2
Primary Efficacy Endpoint
The primary efficacy endpoint is clinical resolution status (defined as absence [ie, a score of 0] 
of bulbar conjunctival injection and ocular conjunctival discharge) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo.
All efficacy analyses will be performed on the mITT population and presented by treatment 
groups. There is a single primary comparison for the single primary endpoint. Therefore, no 
adjustment of multiplicity is needed for the hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 5) will be 
compared between the SHP640 and placebo group. The comparison will be based on the 
proportion of subjects with clinical resolution in the study eye at Visit 3 (Day 5) using Fisher’s 
Exact test at 2-sided 0.0499 significance level. 
If subjects have missing clinical resolution status at Visit 3 (Day 5), then the last post-baseline 
observation will be carried forward for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with 
clinical resolution in the study eye between SHP640 ophthalmic solution and placebo with the 
alternative of the non-zero difference in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 2-sided Fisher’s Exact 
test at 4.99% level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical 
method(s) including other methods of imputation of missing data. Sensitivity analyses may be 
conducted in the ITT population in addition to the mITT. In addition, descriptive statistics will 
be generated for the primary efficacy endpoint by treatment within the overall pediatric 
population (ie, birth to 18 years) and within each pediatric age stratum (<6 years and 6 to 
<18 years) in mITT. A detailed plan for primary analysis including additional sensitivity 
analyses will be described in the SAP.


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9.8.3
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoint is bacterial eradication status (defined as absence of all 
bacterial species present at or above pathological threshold at baseline) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo.
All efficacy analyses will be performed on the mITT population and presented by treatment 
groups. In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary 
hypotheses will be tested sequentially. Each hypothesis will be tested using Fisher’s Exact test at 
2-sided 4.99% level with null hypothesis of no difference in the proportion of subjects for the 
endpoint between the 2 treatment groups. 
First, the primary efficacy endpoint will be tested. Only if the null hypothesis for the primary 
efficacy endpoint is rejected at 4.99% level, then the key secondary efficacy endpoint of bacterial 
eradication will be tested to compare the proportion of subjects with bacterial eradication 
between the SHP640 and placebo treatment group. If subjects have missing bacterial eradication 
status at Visit 3 (Day 5), then the last post-baseline observation will be carried forward for the 
determination of bacterial eradication of the study eye. 
Sensitivity analyses will also be done on key secondary efficacy endpoints using similar methods 
as described above. In addition, descriptive statistics will be generated for the key secondary 
efficacy endpoint by treatment within the overall pediatric population (ie, birth to 18 years) and 
within each pediatric age stratum (<6 years and 6 to <18 years) in the mITT. Details on the 
analyses will be described in the SAP.
9.8.4
Secondary Efficacy Endpoints
All secondary efficacy analyses will be performed on the mITT population and presented by 
treatment group. No hypothesis testing is planned for the secondary efficacy endpoints. All 
secondary efficacy endpoint will be summarized by treatment groups using descriptive statistics 
at each assessment visit. Continuous endpoints will be summarized by number of subjects (n), 
mean, median, standard deviation, minimum, maximum, and confidence intervals (CIs). Binary 
endpoints will be summarized by number of subjects (n), frequencies, proportions, and CIs. Time 
to event endpoint will be summarized by Kaplan-Meier survival estimates.
Secondary efficacy endpoints are defined as follows:

Clinical resolution status of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12) in the study eye

Bacterial eradication status (defined as absence of all bacterial species present at or above 
pathological threshold at baseline) as assessed by bacterial culture at Visits 2 (Day 3), 4 
(Day 8), and 5 (Day 12) in the study eye

Absolute and change from baseline of the individual clinical signs score (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12) in the study eye


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
The global clinical score (defined as the sum of bulbar conjunctival injection and ocular 
conjunctival discharge) and change from baseline in the global clinical score at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with 
neither injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), 
and 5 (Day 12) in the study eye

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), 
and 5 (Day 12) in the study eye

Use of rescue medication
9.8.5
Exploratory Efficacy Endpoints
The ocular discomfort endpoints will be evaluated by absolute and change from baseline of 
ocular discomfort scores (or by the binary ocular discomfort endpoint for children younger than 
8 years of age) due to conjunctivitis symptoms at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12) (mITT population and ITT population). 
No hypothesis testing is planned for the exploratory efficacy endpoint. Exploratory endpoints 
will be summarized using methods similar to secondary endpoints.
9.9
Safety Analyses
Safety data will be presented for the safety population by treatment group and overall.
Safety data collected at baseline prior to treatment (Visit 1/Day 1) will be used as the baseline 
value for safety analysis.
Adverse events, including those suggestive of any local tolerability issues, will be coded using 
the Medical Dictionary for Regulatory Activities. The number of subjects and percentage with a 
TEAE as well as the number of TEAEs will be calculated overall, by system organ class, by 
preferred term, and by treatment group. Treatment-emergent adverse events will be further 
summarized by severity and relationship to investigational product. Adverse events related to 
investigational product, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized and listed.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or a 
non-ocular AE.


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The following safety endpoints will be descriptively summarized by treatment group at each 
applicable visit:

BCVA

Slit lamp biomicroscopy

Lid 

Conjunctiva 

Cornea 

Anterior chamber 

Iris

Lens 

Non-dilated/dilated fundus examination

Vitreous 

Optic nerve 

Macula 

Urine pregnancy testing (for females of childbearing potential)
9.10
Other Analyses
No other analyses are planned in this study.


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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, European Union 
(EU) Directive 2001/20/EC and its updates, and local ethical and legal requirements.
In case of substantial amendment, approval from the Competent Regulatory Authority will be 
sought before implementation. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC and its updates, as well as all applicable national and local laws and 
regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.


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10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study that has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC and its updates, and applicable regulatory requirements and 
guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 


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The coordinating principal investigator will be assigned and selected based on the extent of their 
involvement in the study and experience in the therapeutic area.
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs to ensure accurate and timely information is provided at all 
phases during the study may be done by the sponsor, applicable CRO, investigator, or, for 
multicenter studies, coordinating principal investigator according to national provisions and will 
be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data. All corrections to the eCRF must indicate the reason for 
change. If corrections are made after the review and signature by the investigator, he or she must 
be made aware of the change, and his or her awareness must be documented by re-signing the 
eCRF.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include but are not limited to the 
subject’s medical file, scales, ODS, and documented results of AdenoPlus test results.


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All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) will check the CRF 
entries against the source documents. The consent form includes a statement by which the
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
European Medicines Agency (EMA), United Kingdom Medicines and Healthcare products 
Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation, or honoraria; any proprietary interest in investigational product; and any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP.


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Each subject or the subject’s legally authorized representative, as applicable, is requested to sign 
and date the subject informed consent form or a certified translation if applicable, after the 
subject has received and read (or been read) the written subject information and received an 
explanation of what the study involves, including but not limited to the objectives, potential 
benefits and risk, inconveniences, and subject’s rights and responsibilities. A copy of the 
informed consent and assent documentation (ie, a complete set of subject information sheets and 
fully executed signature pages) must be given to the subject or the subject’s legally authorized 
representative, as applicable. This document may require translation into the local language. 
Signed consent forms must remain in each subject’s study file and must be available for 
verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent(s)/guardian/legally authorized representative/caregiver of the safe, responsible 
storage and administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form and assent form, 
where applicable, that was reviewed by the IRB/EC and received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents.


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For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the CRO.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP640; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, other information (eg, initials and 
date of birth if the local law permits) may also be collected and used to assist the sponsor to 
verify the accuracy of the data (eg, to confirm that laboratory results have been assigned to the 
correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to 
and used in other countries that may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.


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All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.


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11.
REFERENCES
American Academy of Pediatrics 2016. Visual system assessment in infants, children, and young 
adults by pediatricians. Pediatrics, 137, 28-30.
Azari, A. A. & Barney, N. P. 2013. Conjunctivitis: a systematic review of diagnosis and 
treatment. Jama, 310, 1721-9.
Betadine 2004. Betadine Prescribing Information.
Capriotti, J. A., Stewart, K. P. & Pelletier, J. 2010. The unique challenges of viral conjunctivitis -
Its similarities to bacterial infection belie key differences that impact clinical care 
[Online]. Ophthalmology Management. Available: 
http://www.ophthalmologymanagement.com/articleviewer.aspx?articleid=104651
[Accessed].
CDC. 2010. Conjunctivitis (pink eye) [Online]. Centers for Disease Control and Prevention. 
Available: http://www.cdc.gov/conjunctivitis/clinical.html [Accessed].
Chen, C. J. & Starr, C. E. 2008. Epidemiology of gram-negative conjunctivitis in neonatal 
intensive care unit patients. Am J Ophthalmol, 145, 966-970.e2.
Dias, C., Gonçalves, M. & João, A. 2013. Epidemiological study of hospital-acquired bacterial 
conjunctivitis in a level III neonatal unit. Sci World J, 1-5.
Donahue, S. P. & Baker, C. N. 2016. Procedures for the Evaluation of the Visual System by 
Pediatricians. Pediatrics, 137.
Ford, E., Nelson, K. E. & Warren, D. 1987. Epidemiology of epidemic keratoconjunctivitis. 
Epidemiol Rev, 9, 244-61.
Gordon, Y. J., Gordon, R. Y., Romanowski, E. & Araullo-Cruz, T. P. 1993. Prolonged recovery 
of desiccated adenoviral serotypes 5, 8, and 19 from plastic and metal surfaces in vitro. 
Ophthalmology, 100, 1835-9; discussion 1839-40.
Haas, J., Larson, E., Ross, B., See, B. & Saiman, L. 2005. Epidemiology and diagnosis of 
hospital-acquired conjunctivitis among neonatal intensive care unit patients. Pediatr 
Infect Dis J, 24, 586-589.
Leibowitz, H. M. 1991. Antibacterial effectiveness of ciprofloxacin 0.3% ophthalmic solution in 
the treatment of bacterial conjunctivitis. American Journal of Ophthalmology, 112, 29S-
33S.
Maxidex 2007. Maxidex Prescribing Information.
Mehta, C. R. & Pocock, S. J. 2011. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Statistics in medicine, 30, 3267-84.
Nauheim, R. C., Romanowski, E. G., Araullo-Cruz, T., Kowalski, R. P., Turgeon, P. W., Stopak, 
S. S. & Gordon, Y. J. 1990. Prolonged recoverability of desiccated adenovirus type 19 
from various surfaces. Ophthalmology, 97, 1450-3.
O'Brien, T. P., Jeng, B. H., McDonald, M. & Raizman, M. B. 2009. Acute conjunctivitis: truth 
and misconceptions. Curr Med Res Opin, 25, 1953-61.
Patel, P. B., Diaz, M. C. G., Bennett, J. E. & Attia, M. W. 2007. Clinical features of bacterial 
conjunctivitis in children. Clin Investigations, 1-5.
Pelletier, J. S., Stewart, K., Trattler, W., Ritterband, D. C., Braverman, S., Samson, C. M., Liang, 
B. & Capriotti, J. A. 2009. A combination povidone-iodine 0.4%/dexamethasone 0.1% 
ophthalmic suspension in the treatment of adenoviral conjunctivitis. Adv Ther, 26, 776-
83.


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Pelletier, M. R., Casella, L. G., Jones, J. W., Adams, M. D., Zurawski, D. V., Hazlett, K. R., Doi, 
Y. & Ernst, R. K. 2013. Unique structural modifications are present in the 
lipopolysaccharide from colistin-resistant strains of Acinetobacter baumannii. Antimicrob 
Agents Chemother, 57, 4831-40.
Pocock, S. J. & Simon, R. 1975. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 31, 103-15.
Rours, I. G. I. J. G., Hammerschlag, M. R., Ott, A., De Faber, T. J. T. H. N., Verbrugh, H. A., de 
Groot, R. & Verkooyen, R. P. 2008. Chlamydia trachomatis as a cause of neonatal 
conjunctivitis in Dutch infants. Pediatrics, 121, e321.
Statham, M. O., Sharma, A. & Pane, A. R. 2008. Misdiagnosis of acute eye diseases by primary 
health care providers: incidence and implications. Med J Aust, 189, 402-4.
Visscher, K. L., Hutnik, C. M. & Thomas, M. 2009. Evidence-based treatment of acute infective 
conjunctivitis: Breaking the cycle of antibiotic prescribing. Can Fam Physician, 55, 
1071-5.


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12.
APPENDICES




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APPENDIX 2
SCALES AND ASSESSMENTS
All scales assessments referenced in the protocol, including procedural instructions for the 
investigator, are in the Study Operations Manual and the Laboratory Manual (provided upon 
request).

Prot_001.pdf: 
PROTOCOL SHP640-303
TITLE:
A Phase 3, Multi-center, Randomized, Double-Masked Study to 
Evaluate the Clinical Efficacy and Safety of SHP640 (PVP-Iodine 0.6% 
and Dexamethasone 0.1%) Ophthalmic Suspension Compared to 
Placebo in the Treatment of Bacterial Conjunctivitis
DRUG:
SHP640
IND:
75,723
EUDRACT NO:
2016-003361-25
SPONSOR:
Shire
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 27 September 2016
Amendment 1: 28 November 2016
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire




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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to the Shire Global Pharmacovigilance and Risk Management 
Department. Applicable fax numbers and e-mail address can be found on the form (sent under 
separate cover). A copy of this form must also be sent to the contract research organization 
(CRO)/Shire medical monitor by fax or e-mail using the details below.
Fax: 
Email: 
For protocol- or safety-related issues in the United States (US) and North American region, 
the investigator must contact the Shire medical monitor:
, MBBS, DPM, MS
Primary telephone number:
Fax:
Alternate number:
For protocol- or safety-related issues in regions other than North America, the investigator 
must contact the Quintiles 24/7 Emergency Contact center:
Primary telephone number:
Alternate number:


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA),


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TABLE OF CONTENTS
1.
BACKGROUND INFORMATION.......................................................................................21
1.1
Indication and Current Treatment Options...............................................................21
1.2
Product Background and Clinical Information ........................................................21
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................22
2.1
Rationale for the Study.............................................................................................22
2.2
Study Objectives ......................................................................................................22
2.2.1
Primary Objective..................................................................................................22
2.2.2
Key Secondary Objective ......................................................................................22
2.2.3
Secondary Objectives.............................................................................................22
2.2.4
Exploratory Objectives ..........................................................................................23
3.
STUDY DESIGN ...................................................................................................................24
3.1
Study Design and Flow Chart ..................................................................................24
3.2
Duration and Study Completion Definition .............................................................24
3.3
Sites and Regions .....................................................................................................25
4.
STUDY POPULATION.........................................................................................................26
4.1
Inclusion Criteria......................................................................................................26
4.2
Exclusion Criteria.....................................................................................................27
4.3
Reproductive Potential .............................................................................................28
4.3.1
Female Contraception............................................................................................28
4.4
Discontinuation of Subjects .....................................................................................29
4.4.1
Reasons for Discontinuation..................................................................................30
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................30
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................31
5.1
Prior Treatment ........................................................................................................31
5.2
Concomitant Treatment............................................................................................31
5.2.1
Permitted Treatment...............................................................................................31
5.2.2
Prohibited Treatment .............................................................................................31
6.
INVESTIGATIONAL PRODUCT ........................................................................................33
6.1
Identity of Investigational Product...........................................................................33
6.1.1
Masking the Treatment Assignment ......................................................................33
6.1.2
Commercially Obtained Investigational Product...................................................33
6.2
Administration of Investigational Product(s)...........................................................33
6.2.1
Interactive Response Technology for Investigational Product Management ........33
6.2.2
Allocation of Subjects to Treatment ......................................................................33
6.2.3
Dosing....................................................................................................................34
6.2.4
Unmasking the Treatment Assignment..................................................................34


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6.3
Labeling, Packaging, Storage, and Handling ...........................................................34
6.3.1
Labeling .................................................................................................................34
6.3.2
Packaging...............................................................................................................35
6.3.3
Storage ...................................................................................................................35
6.3.4
Special Handling....................................................................................................36
6.4
Drug Accountability.................................................................................................36
6.5
Subject Compliance..................................................................................................37
7.
STUDY PROCEDURES........................................................................................................38
7.1
Study Schedule.........................................................................................................38
7.1.1
Visit 1 (Day 1) .......................................................................................................38
7.1.2
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8) ............................................................40
7.1.3
Visit 5 (End of Study or Early Termination) .........................................................40
7.1.4
Additional Care of Subjects after the Study ..........................................................40
7.2
Study Evaluations and Procedures ...........................................................................40
7.2.1
Demographic and Other Baseline Characteristics .................................................40
7.2.1.1
Demographics.........................................................................................40
7.2.1.2
Medication and Medical History............................................................40
7.2.1.3
AdenoPlus Test ......................................................................................41
7.2.2
Efficacy..................................................................................................................41
7.2.2.1
Clinical Resolution.................................................................................41
7.2.2.2
Bacterial Eradication..............................................................................41
7.2.3
Safety .....................................................................................................................42
7.2.3.1
Best Corrected Visual Acuity.................................................................42
7.2.3.2
Slit Lamp Biomicroscopy.......................................................................42
7.2.3.3
Non-dilated/Dilated Fundus Examination..............................................43
7.2.3.4
Adverse Event Collection.......................................................................43
7.2.3.5
Microbiology Laboratory Evaluations ...................................................44
7.2.3.6
Pregnancy Test .......................................................................................44
7.2.3.7
Health-related Quality of Life Assessments...........................................44
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................45
8.1
Definition of Adverse Events, Period of Observation, and Recording of 
Adverse Events.........................................................................................................45
8.1.1
Severity Categorization..........................................................................................45
8.1.2
Relationship Categorization...................................................................................46
8.1.3
Outcome Categorization ........................................................................................46
8.1.4
Symptoms of the Disease Under Study .................................................................46
8.1.5
Pregnancy...............................................................................................................47
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................47


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8.2
Serious Adverse Event Procedures ..........................................................................48
8.2.1
Reference Safety Information................................................................................48
8.2.2
Reporting Procedures.............................................................................................48
8.2.3
Serious Adverse Event Definition .........................................................................49
8.2.4
Serious Adverse Event Collection Time Frame.....................................................49
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................49
8.2.6
Fatal Outcome........................................................................................................50
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................50
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................51
9.1
Data Collection.........................................................................................................51
9.2
Clinical Data Management.......................................................................................51
9.3
Data Handling Considerations..................................................................................51
9.4
Statistical Analysis Process......................................................................................51
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......52
9.6
Sample Size Calculation and Power Considerations................................................52
9.7
Study Population ......................................................................................................53
9.8
Efficacy Analyses.....................................................................................................53
9.8.1
Study Eye Designation...........................................................................................53
9.8.2
Primary Efficacy Endpoint ....................................................................................54
9.8.3
Key Secondary Efficacy Endpoints .......................................................................54
9.8.4
Secondary Efficacy Endpoints...............................................................................55
9.8.5
Exploratory Efficacy Endpoints.............................................................................56
9.9
Safety Analyses........................................................................................................56
9.10
Other Analyses .........................................................................................................57
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................58
10.1
Sponsor’s Responsibilities .......................................................................................58
10.1.1 Good Clinical Practice Compliance.......................................................................58
10.1.2 Indemnity/Liability and Insurance.........................................................................58
10.1.3 Public Posting of Study Information......................................................................58
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................59
10.1.5 Study Suspension, Termination, and Completion..................................................59
10.2
Investigator’s Responsibilities .................................................................................59
10.2.1 Good Clinical Practice Compliance.......................................................................59
10.2.2 Protocol Adherence and Investigator Agreement..................................................60
10.2.3 Documentation and Retention of Records.............................................................60
10.2.3.1
Case Report Forms.................................................................................60


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10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................60
10.2.3.3
Audit/Inspection.....................................................................................61
10.2.3.4
Financial Disclosure...............................................................................61
10.3
Ethical Considerations..............................................................................................61
10.3.1 Informed Consent...................................................................................................61
10.3.2 Institutional Review Board or Ethics Committee..................................................62
10.4
Privacy and Confidentiality......................................................................................63
10.5
Study Results/Publication Policy .............................................................................63
11. REFERENCES .......................................................................................................................65
12. APPENDICES ........................................................................................................................67


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LIST OF TABLES
Table 1
Schedule of Assessments .........................................................................................19
Table 2 Common Excluded Treatments and Associated Washout Periods ..........................32
LIST OF FIGURES
Figure 1 SHP640-303 Study Design.......................................................................................24
LIST OF APPENDICES
Appendix 1
Protocol History .....................................................................................68
Appendix 2
Scales and Assessments .........................................................................71


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LIST OF ABBREVIATIONS
AAP
American Academy of Pediatrics
AE
adverse event
BCVA
best corrected visual acuity
CFU
colony-forming unit
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
EC
ethics committee
eCRF
electronic case report form
EMA
European Medicines Agency
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
IA
interim analysis
ICH
International Conference on Harmonisation
IMP
investigational medicinal product
IOP
intraocular pressure
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
mITT
modified intent-to-treat
MRSA
methicillin-resistant Staphylococcus aureus
NCS
not clinically significant
NF
National Formulary
ODS
ocular discomfort scale
PVP-I
povidone-iodine


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QID
4 times a day
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment-emergent adverse event
US
United States
USP
United States Pharmacopeia
VA
visual acuity
VBR
Validated Bulbar Redness


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STUDY SYNOPSIS
Protocol number: SHP640-303
Drug: SHP640
Title of the study: A Phase 3, Multi-center, Randomized, Double-Masked Study to Evaluate the Clinical Efficacy 
and Safety of SHP640 (PVP-Iodine 0.6% and Dexamethasone 0.1%) Ophthalmic Suspension Compared to Placebo 
in the Treatment of Bacterial Conjunctivitis
Number of subjects (total and for each treatment arm):
Total subjects: Approximately 721
SHP640 treatment arm: Approximately 309
Povidone-iodine (PVP-I) treatment arm: Approximately 103
Placebo treatment arm: Approximately 309 
Investigator(s): multicenter study
Site(s) and Region(s): 
The study will be conducted in approximately 90 sites across North America, South America, Asia/Pacific, and 
Europe.
Study period (planned):
December 2016 to March 2018
Clinical phase:
3
Objectives:
Primary:
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical resolution (defined as 
absence of bulbar conjunctival injection and ocular conjunctival discharge) compared with placebo in the treatment 
of subjects with bacterial conjunctivitis in the study eye at Visit 3 (Day 5). 
Secondary:
The key secondary objective of this study is to evaluate the efficacy of SHP640 based on bacterial eradication 
(defined as absence of all bacterial species present at or above pathological threshold at baseline) compared with 
placebo in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 (Day 5).
Secondary objectives of this study are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints:

Clinical resolution of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12)

Bacterial eradication at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12)

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival injection and ocular 
conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

The global clinical score (sum of bulbar conjunctival injection and ocular conjunctival discharge) and change 
from baseline in the global clinical score at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12)

Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither injection nor 
discharge having a score of 2 at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the treatment of subjects 


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with bacterial conjunctivitis

Use of rescue medication
Rationale:
The clinical presentation of conjunctivitis is often nonspecific, and differential diagnosis of different types of 
conjunctivitis can be challenging (Azari and Barney 2013; O’Brien et al. 2009). Diagnostic testing to differentiate 
the underlying cause of infection is rarely performed in a clinical setting; misdiagnosis can occur in up to 50% of 
cases, which often results in improper antibiotic treatment (Visscher et al. 2009). Incorrect treatment can not only 
increase healthcare costs from unnecessary antibiotic prescriptions and repeat office visits but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or methicillin-resistant Staphylococcus 
aureus). In addition, there is also a risk of overuse and misuse of antibiotics, which are ineffective in the treatment 
of viral infections (Statham et al. 2008). An unmet medical need therefore exists for a safe and efficacious treatment 
that addresses both bacterial and adenoviral conjunctivitis, 2 of the leading causes of acute infectious conjunctivitis. 
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, with 
dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious and inflammatory 
components of adenoviral and bacterial conjunctivitis.
Investigational product, dose, and mode of administration:
The drug product is SHP640 (0.1% dexamethasone and 0.6% PVP-I) ophthalmic suspension.
The comparators are placebo ophthalmic solution and 0.6% PVP-I ophthalmic solution.
Subjects will instill 1 drop of investigational product in each eye 4 times daily (with a minimum of 2 hours between 
doses) for 7 days.
Methodology:
Once screening and baseline assessments are complete and subjects are confirmed eligible to enroll in the study, 
subjects will be randomized, and investigational product will be administered on the same day (Day 1). The first 
dose will be administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a 
day for 7 days. Additional visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). The study 
will last up to 13 days. 
Inclusion and exclusion criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions (by 
the parent(s), guardian, or legally authorized representative, if applicable).
2.
Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), guardian, or 
legally    authorized representative(s) informed consent (and assent, if applicable) to participate in the 
study.
3.
Subjects of any age at Visit 1 (Note: subjects <3 months of age at Visit 1 must have been full-term, ie 
≥37 weeks gestational age at birth).
4.
Have a negative AdenoPlus® test in both eyes within 24 hours of Visit 1 or at Visit 1.
5.
Have a clinical diagnosis of suspected bacterial conjunctivitis in at least 1 eye confirmed by the 
presence of the following minimal clinical signs and symptoms in that same eye:
5.1. Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤3 days prior to Visit 1
5.2. Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection Scale
5.3. Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale


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6.
Be willing to discontinue contact lens wear for the duration of the study.
7.
Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as measured using 
an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will be assessed by an age 
appropriate method in accordance with the AAP Policy Statement for Visual System Assessment in 
Infants, Children, and Young Adults by Pediatricians (Donahue and Baker 2016; American Academy 
of Pediatrics 2016). The policy statement recommends formal vision screening can begin at 3 years of 
age. VA measurements for children under the age of 3 will be done at the discretion of the investigator. 
If not done, child should be able to fixate on and follow a moving object, except subjects <2 months of 
age who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion of 
investigator. 
8.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of non-childbearing potential.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Current or recurrent disease that could affect the action, absorption, or disposition of the 
investigational product, or clinical or laboratory assessments, per investigator’s discretion.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may make the 
subject unlikely to fully complete the study, or any condition that presents undue risk from the 
investigational product or procedures.
3.
Have known or suspected intolerance or hypersensitivity to the investigational product, closely related 
compounds, or any of the stated ingredients. 
4.
Prior enrollment in a FST-100 or SHP640 clinical study.
5.
Subjects who are employees, or immediate family members of employees (who are directly related to 
study conduct), at the investigational site.
6.
Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned for the 
period of the study.
7.
Have a preplanned overnight hospitalization during the period of the study.
8.
Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, iritis, 
ulcerative keratitis, chronic blepharoconjunctivitis), other than bacterial conjunctivitis.
9.
Have active or a history of ocular herpes.
10. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with the 
diagnosis of ocular allergy, toxic conjunctivitis, or non-bacterial ocular infection (eg, viral, fungal, 
acanthamoebal, other parasitic).
11. Neonates or infants (ie. subjects less than 12 months of age) who have suspected or confirmed (based 
on the result of any test conducted prior to screening) conjunctivitis of gonococcal, chlamydial, 
herpetic or chemical origin.
12. Neonates or infants (ie. subjects less than 12 months of age) whose birth mothers had any sexually 
transmitted disease within 1 month of delivery or any history of genital herpes.
13. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
14. Presence of any significant ophthalmic condition (eg, Retinopathy of Prematurity, congenital cataract, 
congenital glaucoma) or other congenital disorder with ophthalmic involvement that could affect study 
variables.
15. Be a known intraocular pressure (IOP) steroid responder, have a known history of glaucoma, be a 
glaucoma suspect, or have a known history of an elevated IOP >21 mmHg.


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16. Have any known clinically significant optic nerve defects. 
17. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to previous corneal 
trauma or dry eye syndrome; presence of corneal epithelial defect or any significant corneal opacity at Visit 
1.
18. Presence of significant, active condition in the posterior segment that requires invasive treatment (eg, 
intravitreal treatment with vascular endothelial growth factor inhibitors or corticosteroids) and may 
progress during the study participation period. 
19. Have used any topical ocular or systemic antibiotics within ≤7 days of enrollment. 
20. Have used any topical ocular non-steroidal anti-inflammatory drugs within ≤1 day of enrollment.
21. Have used any topical ophthalmic steroids in the last ≤14 days.
22. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 days 
prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no anticipated change in 
dose for the duration of the study. Topical dermal steroids are allowed except in the periocular area.
23. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
24. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all topical 
ophthalmic products for the duration of the study. Use of hot or cold compresses is also not permitted 
during the study.
25. Have any significant ocular disease (eg, Sjogren’s syndrome) or any uncontrolled systemic disease or 
debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted diseases/infections, 
diabetes, or cystic fibrosis) that may affect the study parameters, per investigator’s discretion.
26. Any known history of immunodeficiency disorder or known active conditions predisposing to 
immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of active 
hepatitis A (anti-hepatitis A virus immunoglobulin M), or organ or bone marrow transplantation.
27. Within 30 days prior to the first dose of investigational product:
28. Have used an investigational product or device, or
29. Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s opinion, 
may impact this Shire-sponsored study.
Maximum duration of subject involvement in the study:
Subject participation will last up to 13 days.
Screening, randomization, and the first treatment administration will occur at Visit 1 (Day 1). 
Additional visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). 
All follow-up procedures will be conducted at Visit 5 (Day 12).
Endpoints and statistical analysis:
Primary Efficacy Endpoint:
Clinical resolution status (defined as absence of bulbar conjunctival injection and ocular conjunctival discharge) in 
the study eye at Visit 3 (Day 5) between SHP640 and placebo.
Key Secondary Efficacy Endpoints:
Bacterial eradication status (defined as absence of all bacterial species present at or above pathological threshold at 
baseline) in the study eye at Visit 3 (Day 5) between SHP640 and placebo.
Secondary Efficacy Endpoints:


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
Clinical resolution status of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) in the study 
eye

Bacterial eradication status (defined as absence of all bacterial species present at or above pathological 
threshold at baseline) as assessed by bacterial culture at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) in the study 
eye 

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival injection and ocular 
conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye 

The global clinical score (defined as the sum of bulbar conjunctival injection and ocular conjunctival discharge) 
and change from baseline in the global clinical score at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in 
the study eye 

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12) in the study eye 

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with neither injection nor 
discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye 

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in 
the study eye 

Use of rescue medication 
Safety Endpoints:

BCVA

Slit lamp biomicroscopy 

Non-dilated/dilated fundus examination

Urine pregnancy testing (for females of childbearing potential)

Adverse events (AEs)
Statistical Methods:
The analyses on primary, key secondary, secondary, and exploratory efficacy endpoints will be performed on the 
modified intent-to-treat (mITT) population (unless specified otherwise) and will be presented by treatment group. 
Additional sensitivity analyses may be conducted on the intent-to-treat (ITT) population. Safety analyses will be 
conducted on the safety population.
For both efficacy and safety analyses, baseline is defined as the assessments taken prior to treatment at Visit 1 (Day 
1).
Analysis Populations:
The safety population will include all subjects who receive at least 1 dose of investigational product.
The ITT population will include all randomized subjects. 
The mITT population consists of a subset of the ITT population who receive at least 1 dose of investigational 
product and have a positive bacterial culture (presence of 1 or more bacterial species at or above pathological 
threshold) at baseline in the study eye.
Designation of Study Eye:
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a score of at least 1 for 
both ocular  conjunctival discharge and bulbar conjunctival redness at baseline (baseline is defined as the 
assessments taken prior to treatment at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive bacterial culture (presence of 1 or more bacterial 
species at or above pathological threshold) at baseline or both eyes eligible and both with a non-positive 


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bacterial culture (absence of any bacterial species at or above pathological threshold) at baseline, the study eye 
will be the eye with the highest global clinical score (sum of bulbar conjunctival injection and ocular 
conjunctival discharge) at baseline. If both eyes have the same global clinical score at baseline, then the study 
eye will be the right eye.

For subjects with both eyes eligible with a positive bacterial culture in one eye at baseline, the baseline bacterial 
culture positive eye will be the study eye.

For subjects with only 1 eligible eye, the eligible eye will be the study eye irrespective of its baseline bacterial 
culture status.
Primary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. There is a single primary 
comparison for the single primary endpoint. Therefore, no adjustment of multiplicity is needed for the hypothesis 
testing for the primary objective.
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 5) will be compared between the 
SHP640 and placebo group. The comparison will be based on the proportion of subjects with clinical resolution in 
the study eye at Visit 3 (Day 5) using Fisher’s Exact test at 2-sided 0.05 significance level.
If subjects have missing clinical resolution status at Visit 3 (Day 5), then the last post-baseline observation will be 
carried forward for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with clinical resolution in the 
study eye between SHP640 ophthalmic Solution and placebo with the alternative of the non-zero difference in the 
proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 2-sided Fisher’s Exact test at 5% level of 
significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical method(s) including 
methods of imputation of missing data. Sensitivity analyses may be conducted in the ITT in addition to the mITT.
Key Secondary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. The key secondary efficacy 
endpoint of this study is bacterial eradication status in the study eye at Visit 3 (Day 5) between SHP640 and placebo. 
In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary hypotheses will be tested 
sequentially. Each hypothesis will be tested using Fisher’s Exact test at 2-sided 5.0% level with null hypothesis of 
no difference in the proportion of subjects for the endpoint between the 2 treatment groups. 
First, the primary efficacy endpoint will be tested. Only if the null hypothesis for the primary efficacy endpoint is 
rejected at 5.0% level, then the key secondary efficacy endpoint of bacterial eradication will be tested to compare 
the proportion of subjects with bacterial eradication between the SHP640 and placebo treatment group. If subjects 
have missing bacterial eradication at Visit 3 (Day 5), then the last post-baseline observation will be carried forward 
for the determination of bacterial eradication of the study eye. 
Sensitivity analyses will also be done on the key secondary efficacy endpoint using similar methods as described 
above.
Secondary Efficacy Analyses:
No hypothesis testing is planned for the secondary efficacy endpoints. All secondary efficacy endpoints will be 
summarized by treatment groups using descriptive statistics at each assessment visit. Continuous endpoints will be 
summarized by number of subjects (n), mean, median, standard deviation, minimum, maximum, and confidence 
intervals (CIs). Binary endpoints will be summarized by number of subjects (n), frequencies, proportions, and CIs.
Time to event endpoint will be summarized by Kaplan-Meier survival estimates.
Safety Analyses:
Safety data will be presented for the safety population by treatment group and overall.


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Safety data collected at baseline prior to treatment (Visit 1/Day 1) will be used as the baseline value for safety 
analysis.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The number of subjects and 
percentage with a treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated 
overall, by system organ class, by preferred term, and by treatment group and overall. TEAEs will be further 
summarized by severity and relationship to investigational product. AEs related to investigational product, AEs 
leading to withdrawal, serious AEs, and deaths will be similarly summarized and listed. Any AE that occurs after the 
first dose of investigational product instillation will be considered a TEAE.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or a non-ocular AE.
Slit lamp biomicroscopy, non-dilated/dilated fundus exam, BCVA, and urine pregnancy test (for females of 
childbearing potential) will be descriptively summarized by treatment group and overall at each applicable visit.


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Study Schedule
Table 1
Schedule of Assessments
Procedure
(All ocular assessments and procedures 
performed bilaterally)
Visit 1
Screeninga and Baseline
(Day 1)
-1 Day
Visit 2
(Day 3)
Visit 3
(Day 5)
Visit 4
(Day 8)
Visit 5b
(Day 12)
+1 Day
Informed consent/assenta
X
Inclusion/exclusion criteriaa
X
Medical history 
X
Demographics
X
Concomitant medications
X
X
X
X
X
Urine pregnancy test
Xc
Xc
Ocular discomfort scale
X
X
X
X
X
Best corrected visual acuity
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
Bulbar conjunctival injection evaluation
X
X
X
X
X
Ocular conjunctival discharge evaluation
X
X
X
X
X
AdenoPlus® test
Xd
Conjunctival swab for bacterial culturee
X
Xf
Xf
Xf
X
Conjunctival swab for chlamydia and gonorrhea 
detectionl
X
Non-dilated/dilated fundus examinationk
X
X
Randomizationg
X
Dispense investigational producth
X
Instill investigational product
Xh
Xi
Xi
Collect investigational product
X
Xb
Compliance assessment
X
X
X
Xb
Drug accountability
X
Xb
Adverse events
Xj
X
X
X
X


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Table 1
Schedule of Assessments
Procedure
(All ocular assessments and procedures 
performed bilaterally)
Visit 1
Screeninga and Baseline
(Day 1)
-1 Day
Visit 2
(Day 3)
Visit 3
(Day 5)
Visit 4
(Day 8)
Visit 5b
(Day 12)
+1 Day
Study completion
X
ET=early termination; 
a Informed consent and confirmation of inclusion/exclusion criteria can be conducted on Day -1; these criteria must be reconfirmed on Day 1.
b If investigational product is discontinued, regardless of the reason, all discontinued subjects should proceed to Visit 5 whenever possible. Subjects who
discontinue the study and proceed to Visit 5 should perform all Visit 5 assessments as well as drug return, compliance, and accountability.
c Women of childbearing potential, prior to enrollment and at exit from the study
d If not previously conducted within 24 hours of Visit 1 (Day 1)
e One swab sample from inferior conjunctival cul-de-sac of each eye will be collected for all bacterial testing.
f Conjunctival swab samples MUST be taken at least 12 hours after the last dose of investigational product at Visits 2, 3, 4, and ET, if applicable.
g All assessments, randomization, and investigational product instillation on Day 1 must take place with sufficient time to allow all 4 Day 1 doses (with a 
minimum of 2 hours between doses).
h The investigational product bottle should be shaken well prior to use at each dosing. The first dose will be administered by site staff on Day 1, and thereafter 
subjects will administer 1 drop in each eye 4 times a day for 7 days.
i Investigational product instillation should only be performed in-office if it is necessary.
j Monitoring for adverse events will begin after informed consent is obtained.
k If a non-dilated fundus exam is not feasible, a dilated examination should be conducted. For each subject, the exam should be conducted the same way (either 
non-dilated or dilated) at both Visits 1 and 5 (or ET). 
l Only for subjects <2 months of age.


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Conjunctivitis affects all populations worldwide of all ages and social strata, irrespective of 
gender. Infectious conjunctivitis (adenoviral and bacterial) represents a serious public health 
issue due to a risk of highly infectious epidemics, lost productivity, significant subject 
discomfort, and, in some cases, permanent visual compromise from long-term, immune-mediated 
sequelae (Capriotti et al., 2010; Ford et al., 1987; Gordon et al., 1993; Nauheim et al., 1990; 
Pelletier et al., 2009). Bacterial conjunctivitis is the second-most common cause of infectious 
conjunctivitis with a viral etiology being the most common cause (Azari and Barney, 2013). 
Bacterial etiology is more common in children, potentially accounting for 50-75% of all 
infectious conjunctivitis cases occurring in children (Azari and Barney, 2013). The condition is 
caused by a wide variety of bacteria, including gram-positive species such as Staphylococcus 
aureus and Streptococcus pneumoniae and gram-negative species such as Haemophilus 
influenzae, Chlamydia trachomatis, and Moraxella catarrhalis (Azari and Barney, 2013; Chen 
and Starr, 2008; CDC, 2010; Dias et al., 2013; Haas et al., 2005; Patel et al., 2007; Rours et al., 
2008). Bacterial conjunctivitis typically lasts for 7 to 10 days, yet, in the absence of adequate 
treatment, it can last for weeks or months.
1.2
Product Background and Clinical Information
SHP640, a novel topical ophthalmic suspension, is currently under development for the treatment 
of infectious conjunctivitis (adenoviral and bacterial).
SHP640 contains 2 active ingredients: povidone-iodine (PVP-I) and dexamethasone. PVP-I is a 
multivalent broad-spectrum local antiseptic with bactericidal and fungicidal properties. The 
effect on vegetative cells of various bacteria and fungi is due to the liberation of free iodine from 
the complex. It is effective against many viruses, protozoa, yeasts, cysts, and spores (Betadine, 
2004). Dexamethasone is a corticosteroid routinely used as a topical ophthalmic suspension for 
the treatment of ocular inflammation. It suppresses the inflammatory response to a variety of 
causes of inflammation (Maxidex, 2007). Both components are currently approved for use in 
other indications (at similar or higher concentrations) and have been shown to be safe and 
efficacious for use on the ocular surface in humans. The combination of PVP-I and 
dexamethasone has been shown to rapidly kill common ocular pathogens, including viruses, 
gram-positive bacteria (including methicillin-resistant Staphylococcus aureus [MRSA]), and 
gram-negative bacteria (Pelletier et al., 2013).
Always refer to the latest version of the SHP640 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy, and safety of SHP640. 


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The clinical presentation of conjunctivitis is often nonspecific, and differential diagnosis of 
different types of conjunctivitis can be challenging (Azari and Barney, 2013; O'Brien et al., 
2009). Diagnostic testing to differentiate the underlying cause of infection is rarely performed in 
a clinical setting; misdiagnosis can occur in up to 50% of cases, which often results in improper 
antibiotic treatment (Visscher et al., 2009). Incorrect treatment can not only increase healthcare 
costs from unnecessary antibiotic prescriptions and repeat office visits, but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or MRSA). In 
addition, there is also a risk of overuse and misuse of antibiotics, which are ineffective in the 
treatment of viral infections (Statham et al., 2008). An unmet medical need therefore exists for a 
safe and efficacious treatment that addresses both bacterial and adenoviral conjunctivitis, 2 of the 
leading causes of acute infectious conjunctivitis.
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, 
with dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious 
and inflammatory components of adenoviral and bacterial conjunctivitis.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical 
resolution (defined as absence of bulbar conjunctival injection and ocular conjunctival discharge) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye 
at Visit 3 (Day 5). 
2.2.2
Key Secondary Objective
The key secondary objective is to evaluate the efficacy of SHP640 based on bacterial eradication 
(defined as absence of all bacterial species present at or above pathological threshold at baseline) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye 
at Visit 3 (Day 5).
2.2.3
Secondary Objectives
The secondary objectives are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints: 

Clinical resolution of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12)

Bacterial eradication at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) 

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12)


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
The global clinical score (sum of bulbar conjunctival injection and ocular conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 5), 4 (Day 8), and 5 (Day 12) 

Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) 

Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither 
injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12) 

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12) 

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the 
treatment of subjects with bacterial conjunctivitis

Use of rescue medication
2.2.4
Exploratory Objectives
The exploratory objectives of this study are as follows: 

To evaluate ocular discomfort due to conjunctivitis symptoms in subjects receiving SHP640 
compared to PVP-I and placebo at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)


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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
SHP640-303 is a global, multicenter, randomized, double-masked, parallel-group, placebo-
controlled study designed to demonstrate the safety and efficacy of SHP640 ophthalmic 
suspension compared to placebo in treating bacterial conjunctivitis. In addition, an exploratory 
arm of PVP-I 0.6% ophthalmic solution will be included.
Approximately 721 subjects will be randomized into the study at Visit 1 (Day 1). Randomization 
will be stratified by age to maintain the randomization ratio among subjects <6 years, 6 to <18 
years, and subjects ≥18 years. Subjects will be randomized 3:1:3 to receive either SHP640, PVP-
I, or placebo within each stratum. 
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced randomization will be used in this study to 
maintain the randomization ratio within each stratum. 
Once screening and baseline assessments are complete and subjects are confirmed eligible to 
enroll in the study, subjects will be randomized, and investigational product will be administered 
on the same day (Day 1). The first dose will be administered by site staff on Day 1, and 
thereafter subjects will administer 1 drop in each eye 4 times a day (QID) for 7 days. Additional 
visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). All follow-up 
procedures will be conducted at Visit 5 (Day 12). The study will last up to 13 days. 
Figure 1 provides the study design.
Figure 1
SHP640-303 Study Design
PVP-I=povidone iodine
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 13 days. The 
study will be completed in approximately 1.5 years. 


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The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit (Visit 5) 
or contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
The study will be conducted in approximately 90 sites across North America, South America, 
Asia/Pacific, and Europe.


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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed. If a subject is younger 
than the legal age of consent (per local laws), the subject’s parent(s), guardian, or legally 
authorized representative will provide written informed consent; the subject will provide verbal 
or written assent as appropriate.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions (by the parent(s), guardian, or legally authorized representative, if applicable).
2. Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), 
guardian, or legally authorized representative(s) informed consent (and assent, if applicable) 
to participate in the study.
3. Subjects of any age at Visit 1 (Note: subjects <3 months of age at Visit 1 must have been 
full-term, ie, ≥37 weeks gestational age at birth).
4. Have a negative AdenoPlus® test in both eyes within 24 hours of Visit 1 or at Visit 1.
5. Have a clinical diagnosis of suspected bacterial conjunctivitis in at least 1 eye confirmed by 
the presence of the following minimal clinical signs and symptoms in that same eye:

Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤3 days prior to 
Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection 
Scale

Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
6. Be willing to discontinue contact lens wear for the duration of the study.
7. Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as 
measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will 
be assessed by an age appropriate method in accordance with the AAP Policy Statement for 
Visual System Assessment in Infants, Children, and Young Adults by Pediatricians 
(Donahue and Baker, 2016; American Academy of Pediatrics, 2016). The policy statement 
recommends formal vision screening can begin at 3 years of age. VA measurements for 
children under the age of 3 will be done at the discretion of the investigator. If not done, child 
should be able to fixate on and follow a moving object, except subjects <2 months of age 
who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion 
of investigator.
8. Male, or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential.


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4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Current or recurrent disease that could affect the action, absorption, or disposition of the 
investigational product, or clinical or laboratory assessments, per investigator’s discretion.
2. Current or relevant history of physical or psychiatric illness, any medical disorder that may
make the subject unlikely to fully complete the study, or any condition that presents undue 
risk from the investigational product or procedures.
3. Have known or suspected intolerance or hypersensitivity to the investigational product, 
closely related compounds, or any of the stated ingredients. 
4. Prior enrollment in a FST-100 or SHP640 clinical study.
5. Subjects who are employees, or immediate family members of employees (who are directly 
related to study conduct), at the investigational site.
6. Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned 
for the period of the study.
7. Have a preplanned overnight hospitalization during the period of the study.
8. Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, 
iritis, ulcerative keratitis, chronic blepharoconjunctivitis), other than bacterial conjunctivitis.
9. Have active or a history of ocular herpes.
10. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with 
the diagnosis of ocular allergy, toxic conjunctivitis, or non-bacterial ocular infection (eg, 
viral, fungal, acanthamoebal, other parasitic). 
11. Neonates or infants (ie. subjects less than 12 months of age) who have suspected or 
confirmed (based on the result of any test conducted prior to screening) conjunctivitis of 
gonococcal, chlamydial, herpetic or chemical origin.
12. Neonates or infants (ie. subjects less than 12 months of age) whose birth mothers had any 
sexually transmitted disease within 1 month of delivery or any history of genital herpes.
13. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
14. Presence of any significant ophthalmic condition (eg, Retinopathy of Prematurity, congenital 
cataract, congenital glaucoma) or other congenital disorder with ophthalmic involvement that 
could affect study variables.
15. Be a known intraocular pressure (IOP) steroid responder, have a known history of glaucoma, 
be a glaucoma suspect, or have a known history of an elevated IOP >21 mmHg.
16. Have any known clinically significant optic nerve defects. 
17. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to 
previous corneal trauma or dry eye syndrome; presence of corneal epithelial defect or any 
significant corneal opacity at Visit 1.


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18. Presence of significant, active condition in the posterior segment that requires invasive 
treatment (eg, intravitreal treatment with vascular endothelial growth factor inhibitors or 
corticosteroids) and may progress during the study participation period. 
19. Have used any topical ocular or systemic antibiotics within ≤7 days of enrollment. 
20. Have used any topical ocular non-steroidal anti-inflammatory drugs within ≤1 day of 
enrollment.
21. Have used any topical ophthalmic steroids in the last ≤14 days.
22. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 
days prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no 
anticipated change in dose for the duration of the study. Topical dermal steroids are allowed 
except in the periocular area.
23. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
24. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all 
topical ophthalmic products for the duration of the study. Use of hot or cold compresses is 
also not permitted during the study.  
25. Have any significant ocular disease (eg, Sjogren’s syndrome) or any uncontrolled systemic 
disease or debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted 
diseases/infections, diabetes, or cystic fibrosis) that may affect the study parameters, per 
investigator’s discretion.
26. Any known history of immunodeficiency disorder or known active conditions predisposing 
to immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of  
active hepatitis A (anti-hepatitis A virus immunoglobulin M), or organ or bone marrow 
transplantation.
27. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study.
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception throughout the study period. If hormonal contraceptives are used, they should be 
administered according to the package insert. Females of childbearing potential who are not 
currently sexually active must agree to use acceptable contraception, as defined below, if they 
become sexually active during the period of the study.
Female children and adolescent subjects should be either:


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
Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine pregnancy test at Visit 1. Females of 
childbearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Adult female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and ≥age 51 years)

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of childbearing potential with a negative urine pregnancy test at Visit 1 and prior to 
randomization. Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use acceptable methods of contraception. 
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Intrauterine hormone-releasing systems plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam) 

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the screening visit (Visit 1), plus condoms. 
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). 
Rescue treatment with a licensed antibiotic according to the local standard of care should be 
provided to subjects if, in the judgment of the investigator, there is no clinical improvement or 
worsening of their condition to an extent that it would be in the best interest of the subject to be 
treated with an alternate therapy for safety reasons. In such instances, the investigational product 
should be discontinued, Visit 5 evaluations be performed at the time of subject discontinuation
after which rescue treatment will be started.
The investigator is encouraged to discuss withdrawal of a subject from investigational product 
with the medical monitor if necessary.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Visit 5 are to be performed as completely as possible. Whenever possible, all discontinued 


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subjects should also undergo the protocol-specified follow-up (proceed to Visit 5). Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded in the source 
documents. The reason for termination and the date of stopping investigational product must be 
recorded in the case report form (CRF) and source documents.
Subject numbers for subjects who discontinue will not be reused. 
4.4.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF. 
Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol deviation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Physician decision

Study terminated by sponsor

Withdrawal by parent(s)/guardian/legally authorized representative (if applicable)

Other (If “Other” is selected, the investigator must specify on the CRF.)
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.


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5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment received within 30 days prior to the screening visit (Visit 1; or 
pharmacokinetic equivalent of 5 half-lives, whichever is longer) and through the final study 
contact (including protocol-defined follow-up period) must be recorded on the appropriate CRF 
page.
5.1
Prior Treatment
Prior treatment includes all treatment received within 30 days prior to the screening visit 
(Visit 1) (or pharmacokinetic equivalent of 5 half-lives, whichever is longer). Prior treatment 
information must be recorded on the appropriate CRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment other than the investigational production taken 
between the dates of the first dose of investigational product and the end of Visit 5 (the end of 
study visit), inclusive. Concomitant treatment information must be recorded on the appropriate 
CRF page.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
Medications not indicated as prohibited are permitted, including treatments for general 
non-excluded medical conditions.
In the event of an emergency, any needed medications may be prescribed without prior approval, 
but the medical monitor must be notified of the use of any prohibited medications immediately 
thereafter.
5.2.2
Prohibited Treatment
Table 2 details the washout period for common prior treatments that are excluded medications 
for this study. 


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Table 2
Common Excluded Treatments and Associated Washout Periods
Minimum Time Prior to First Dose
Notes
Treatment
30 days 
14 days
7 days
1 day
2 hours
Topical ocular NSAIDs
X
Topical ocular or systemic antivirals
X
Topical ophthalmic steroids
X
Systemic corticosteroid agents
X
Stable use of inhaled or nasal 
corticosteroids
X
Allowed ≥30 days if 
no anticipated dose 
changes during the 
study
Noncorticosteroid immunosuppressive 
agents
X
Topical ophthalmic solutions, 
including tear substitutes, and OTC 
preparations (ie, lid scrubs)
X
Must be able to 
discontinue use for 
the duration of the 
study
NSAID=non-steroidal anti-inflammatory drug; OTC=over-the-counter
Treatments not listed in Table 2 are considered permitted. 


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
Three test products will be used in the clinical development program. The drug product is 
SHP640 (0.1% dexamethasone and 0.6% PVP-I) ophthalmic suspension, the comparator is 0.6% 
PVP-I ophthalmic solution, and the placebo product is placebo ophthalmic solution. Each of 
these test products are manufactured aseptically and filled in sterile plastic ophthalmic bottles. 
The placebo contains 2 additional ingredients relative to the others: benzalkonium chloride, 
United States Pharmacopeia (USP), EP, used as a preservative, and caramel color, National 
Formulary (NF), included to match the dark brown color of the PVP-I active ingredient. 
Additional information on the 3 test products is provided in the current SHP640 investigator’s 
brochure.
6.1.1
Masking the Treatment Assignment
The packaging, appearance, and labeling of the test products will match. Colorant will be added 
to the placebo to match the appearance of SHP640 and the PVP-I ophthalmic solution. Treatment 
assignment will be determined by the randomization schedule.
6.1.2
Commercially Obtained Investigational Product
Not Applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive response technology (IRT) vendor will be used for this study to manage packaged 
investigational medicinal product (IMP) supply, IMP shipments, receipt of IMP at clinical sites, 
randomization of IMP to subjects, expiry tracking, IMP returns, accountability of IMP, and 
emergency unmasking. 
6.2.2
Allocation of Subjects to Treatment 
This is a double-masked, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment is 
automatically assigned by the IRT.
Randomization will be stratified by age to maintain the randomization ratio among subjects <6 
years, 6 to <18 years, and subjects ≥18 years. Subjects will be randomly assigned to receive 


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SHP640, PVP-I 0.6%, or placebo based on a 3:1:3 ratio (SHP640:PVP-I:placebo) within the 
randomization strata.
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced randomization (Pocock and Simon, 1975) will 
be used in this study to maintain the randomization ratio within each stratum. The randomization 
will be done centrally. 
6.2.3
Dosing
Subjects will be instructed to instill 1 drop of investigational product in each eye QID (with a 
minimum of 2 hours between doses) for 7 days.
Prior to administration of the first dose, the bottle should be removed from refrigeration and 
allowed to come to room temperature. The bottle will not be refrigerated before subsequent 
administrations. Storage requirements are discussed in Section 6.3.3.
The investigational product bottle should be shaken well prior to use at each dosing.
In-office dosing will only be performed at the first visit, and additionally if necessary. 
6.2.4
Unmasking the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor as soon as possible after the 
unmasking occurs. 
In the event that the treatment assignment is broken, the date and person who broke the code will 
be recorded by the IRT, and the reason for breaking will be recorded on the CRF. Upon breaking 
the mask, the subject will be withdrawn from the study but should complete Visit 5 (the end of 
study visit) to be followed up for safety purposes. Any code breaks that occur must be reported 
to the sponsor’s medical monitor. 
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and carton identification are applied to the investigational 
product(s) container. 
All investigational product is labeled with a minimum of the following: protocol number, 
investigational product identification number, dosage form, directions for use, storage 
conditions, expiry date (if applicable), batch number and/or packaging reference number, the 
statements “For clinical trial use only” and/or “CAUTION: New Drug – Limited by Federal (or 
US) Law to Investigational Use,” and the sponsor’s name and address. Any additional labeling 


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requirements for participating countries and/or controlled substances will also be included on the 
label, if necessary.
Space is allocated on the label so that the site representative can record the date dispensed, the 
subject’s initials (as permitted based on local laws), and the unique subject number.
Additional labels may, on a case-by-case basis, be applied to the investigational product in order 
to satisfy local or institutional requirements but must not: 

Contradict the clinical study label. 

Obscure the clinical study label. 

Identify the study subject by name. 
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers.
The investigational product bottle will be labeled and then placed into a 1x-labeled carton. This 
carton will then be secured with a tamper seal.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigational product must be stored at the site in a secure, refrigerated area (2-8ºC) 
accessible only to the investigator and his/her designees. The investigational product will be 
administered only to subjects enrolled in the clinical study, in accordance with the conditions 
specified in this protocol.
Undispensed investigational product should be stored under refrigeration at 2-8ºC.
Dispensed investigational product should be stored at room temperature below 30ºC. 
Investigational product should be protected from freezing and exposure to strong light.
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier and initials as permitted based on local laws 
on the investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 


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product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system or a mechanical recording device such as a calibrated chart recorder or by 
manual means, such that both minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required. Such a device (ie, certified min/max 
thermometer) would require manual resetting upon each recording. The sponsor must be notified 
immediately upon discovery of any excursion from the established range. Temperature 
excursions will require site investigation as to cause and remediation. The sponsor will determine 
the ultimate impact of excursions on the investigational product and will provide supportive 
documentation as necessary. Under no circumstances should the product be dispensed to subjects 
until the impact has been determined and the product is deemed appropriate for use by the 
sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
Not Applicable.
6.4
Drug Accountability  
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content, and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All dispensed
investigational product will be documented on the CRFs and/or other investigational product 
record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.


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The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the mask of the study is not compromised.
With the written agreement of the sponsor, at the end of the study all unused stock and 
empty/used investigational product packaging may be destroyed at the site or a local facility. In 
this case, destruction records identifying what was destroyed as well as when and how must be 
obtained with copies provided to the sponsor. Destruction of investigational products must be in 
accordance with local, state, and national laws.
If a site is not approved by the sponsor to destroy the investigational product, all used and unused 
stock is to be sent to a nominated contractor on behalf of the sponsor. Investigational products 
being returned to the sponsor’s designated contractors must be counted and verified by clinical 
site personnel and the sponsor (or designated contractor research organization [CRO]). Validated 
electronic return systems (ie, IRT) may not require a shipment form. Returned investigational 
products must be packed in a tamper-evident manner to ensure product integrity. Contact the 
sponsor for authorization to return any investigational product prior to shipment. Shipment of all 
returned investigational product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Subjects must be instructed to bring their investigational product and empty/used investigational 
product packaging to every visit. The pharmacist/nominated person will record details on the 
drug accountability form.
Subject compliance will be verified verbally during study visits. In cases of non-compliance, the 
investigator should determine if the medical monitor must be contacted for consultation. 


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7.
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Assessments (see Table 1) and must be referred to in conjunction with the 
instructions provided in this section. Procedures or assessments that are not completed or are
performed out of order should be captured as protocol deviations.
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject (as per 
local requirements). If a subject is younger than the legal age of consent (per local laws), the 
subject’s parent(s), guardian, or legally authorized representative will provide written informed 
consent; the subject will provide verbal or written assent as appropriate. There must be 
documentation of consent/assent (as per local requirements) indicating that the subject is aware 
of the investigational nature of the study and the required procedures and restrictions, prior to 
performing any study-related procedures. 
Where applicable, all procedures will be performed in both eyes.
7.1.1
Visit 1 (Day 1)
Screening and baseline/randomization will occur at Visit 1. Visit 1 assessments, beginning with 
informed consent, will be performed as outlined in Table 1.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product. Subjects cannot be rescreened once they have been designated as a 
screen failure.
A urine pregnancy test will be completed for all females of childbearing potential. The results 
will be read by site personnel and recorded in the source documents.
All AEs occurring after signature of informed consent must be recorded in the source documents 
and CRF. 
Prior to randomization, the procedures should be performed in the following order (in both eyes, 
as appropriate):

Informed consent (and assent, if applicable)

Inclusion/exclusion criteria

Medical history

Demographics

Concomitant medications

Urine pregnancy test (for women of childbearing potential)


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
Ocular discomfort scale

BCVA

Slit lamp biomicroscopy

Bulbar conjunctival injection evaluation

Ocular conjunctival discharge evaluation

AdenoPlus® test (if not previously conducted within 24 hours of Visit 1)
If any findings during screening exams do not meet the inclusion/exclusion criteria, the subject is 
not eligible to be randomized. 
Eligible subjects must have a positive response in at least one eye. A positive response is defined 
as meeting ALL of the following criteria in the same eye:

Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤3 days prior to 
Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection 
Scale

Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
Study eye will not be determined at Visit 1. All ophthalmic assessments will be conducted on 
both eyes. Selection of study eye for analyses will be according to the criteria outlined in 
Section 9.8.1.
The procedures should be performed in the following order:

Conjunctival bacterial culture collection (1 swab per eye). An additional swab from each eye 
will be collected in subjects <2 months of age for testing the presence of chlamydia and 
gonorrhea

Non-dilated/dilated fundus examination

Randomization

Dispense and instill investigational product in both eyes by the designated site staff 
investigational product administrator. The investigational product bottle should be shaken 
well prior to use at each dosing.
All assessments, randomization, and investigational product instillation on Day 1 must take place 
with sufficient time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses).


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7.1.2
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8)
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8) assessments will be performed as outlined in Table 1
and as described in the Study Operations Manual. Assessments should be performed in 
descending order as listed.
Subject compliance will be verified verbally during study visits. In cases of non-compliance, the 
investigator should determine if the medical monitor must be contacted for consultation. 
Subjects should not instill investigational product within 12 hours of scheduled study visits. To 
ensure this, subjects should be reminded to not dose the morning of Visits 2, 3, and 4. 
Investigational product instillation should only be performed in-office if it is necessary and 
should be done once all other assessments are completed. Subjects who instill investigational 
product less than 12 hours before study visits will be recorded as protocol deviations.
7.1.3
Visit 5 (End of Study or Early Termination)
Safety follow-up will be conducted at Visit 5 (the end-of-study visit). Visit 5 (Day 12) 
assessments will be performed as outlined in Table 1. Assessments should be performed in 
descending order as listed.
Subjects who discontinue the study and proceed to Visit 5 for early termination should have 
investigational product collected, a compliance assessment, and drug accountability assessed at 
their final visit.
All AEs and serious AEs (SAEs) that are not resolved at the time of Visit 5 or early termination 
will be followed to closure (see Section 8.1).
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
7.2.1.1
Demographics
Demographic information will be collected at Visit 1. Date of birth (where permitted), age, sex, 
race, and ethnicity will be recorded.
7.2.1.2
Medication and Medical History
MEDICATION HISTORY
Refer to Section 5 for full details on collection of prior treatment.
The investigator will categorize treatments as ocular (specified as left eye, right eye, or both 
eyes) or non-ocular-based on the indication for use. Prior treatment information must be recorded 
on the appropriate CRF page. 


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MEDICAL HISTORY
The site must record all clinically or medically relevant information regardless of how much time 
has elapsed since the date of any diagnosis. Medical history will be classified as ocular (specified 
as left eye, right eye or both eyes)  or non-ocular by the investigator. History should include but 
is not limited to: 

History of ocular diseases/conditions 

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, and any other non-ocular diseases/underlying conditions within 
the past year prior to the screening visit (Visit 1)
7.2.1.3
AdenoPlus Test
The AdenoPlus test will be performed at Visit 1 (unless results are available from a test 
performed within 24 hours of Visit 1) as outlined in Table 1. A negative result in both eyes is 
required for enrollment in this study.
The AdenoPlus test is an in-office test that allows for the detection of adenoviral antigens 
directly from human eye fluid. A small tear sample is transferred onto the AdenoPlus test, which 
confirms the presence of adenovirus and the viral form of conjunctivitis. 
Please refer to the Study Operations Manual for a detailed description of the AdenoPlus Test and 
administration.
7.2.2
Efficacy
7.2.2.1
Clinical Resolution
Clinical resolution of bacterial conjunctivitis is defined as the absence (score=0) of bulbar 
conjunctival injection and watery conjunctival discharge in the study eye. Bulbar conjunctival 
injection will be assessed based on a 0-4 scale that uses pictures from the Validated Bulbar 
Redness (VBR) Scale, and watery conjunctival discharge will be assessed based on a 0-3 scale. 
Details of the bulbar conjunctival injection and watery conjunctival discharge scales are located 
in the Study Operations Manual.
7.2.2.2
Bacterial Eradication
Bacterial eradication for an eye is defined as absence of all bacterial species present at or above 
pathological threshold at baseline in that eye. 
Pathological threshold for individual bacterial species will be based on colony-forming unit 
(CFU)/mL threshold levels established by Cagle and modified by Leibowitz for different ocular 
bacterial species found in the specimens collected from each subject (Leibowitz 1991). Bacterial 
species will be determined by Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass 
Spectrometry, using their protein patterns.
Additional details are located in the Study Operations Manual. 


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7.2.3
Safety
Safety assessments will be performed in both eyes.
7.2.3.1
Best Corrected Visual Acuity
The BCVA will be performed prior to slit lamp examination during the study as outlined in
Table 1. 
The complete instructions for performing the BCVA are in the Study Operations Manual. 
Changes in visual acuity (VA) will be assessed for clinical significance. Clinically significant 
changes should be recorded in the source and on the electronic CRF (eCRF) as an AE.
For subjects who are too young to use an ETDRS chart, use an age-appropriate measurement
method in accordance with the AAP Policy Statement for Visual System Assessment in Infants, 
Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American Academy of 
Pediatrics, 2016; located in the Study Operations Manual) The policy statement recommends 
formal vision screening can begin at 3 years of age. VA measurements for children under the age 
of 3 will be done at the discretion of the investigator. If not done, child should be able to fixate 
on and follow a moving object. This is not a requirement in subjects <2 months of age since the 
ability does not develop until about 2 months of age. However, if an infant <2 months of age is 
able to fix and follow, it should be recorded. The enrollment of subjects <2 months of age will be 
based on subject qualifying all other eligibility criteria and Investigator discretion.
7.2.3.2
Slit Lamp Biomicroscopy
Slit lamp biomicroscopy (or handheld slit lamp) will be performed during the study as outlined 
in Table 1. Magnification of the slit lamp will be consistent with standard clinical practice. The 
subject will be seated.
Observations will be graded as normal or abnormal. Abnormal findings will be described, and 
clinically significant abnormalities should be recorded in the source and on the eCRF (in medical 
history at screening; any changes from the screening visit may be recorded as AEs by the 
investigator). Please note the investigator may use his/her discretion to determine whether not 
clinically significant (NCS) and disease progression should be considered AEs). The following 
will be examined at each visit: 

Lids 

Conjunctiva 

Cornea

Anterior chamber

Iris

Lens


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For infants and young children, if the above exams cannot be performed with a slit lamp or a 
hand held slit lamp, an external examination is to be conducted in accordance with the AAP’s
Policy Statement for Visual System Assessment in Infants, Children, and Young Adults by 
Pediatricians (Donahue and Baker, 2016; American Academy of Pediatrics, 2016; located in the 
Study Operations Manual). The examination of lens in these subjects should be conducted at 
Visits 1 and 5 (or ET visit) and graded based on the external examination and red reflex exam 
(Section 7.2.3.3). All other structures listed above will be examined and graded at all visits based 
on the external examination. Observations will be graded as normal or abnormal. Abnormal 
findings will be described.
7.2.3.3
Non-dilated/Dilated Fundus Examination
Fundus examination must be conducted after BCVA, slit lamp biomicroscopy, and conjunctival 
swab for bacterial culture has been collected. 
A non-dilated fundus examination will be performed in all subjects with the exception of infants 
and uncooperative small children during the study as outlined in Table 1.
Observations will be graded as normal or abnormal. Abnormal findings will be described.
The following will be examined:

Vitreous

Optic Nerve

Macula
Clinically significant changes should be recorded in the source and on the eCRF as an AE.
If a non-dilated fundus exam is attempted and is not feasible, a dilated fundus exam should be 
conducted. The test should be conducted the same way (either dilated or non-dilated) at both 
Visits 1 and 5 (or ET).
For infants and small children in whom a fundus examination cannot be done, a red reflex exam 
will be conducted in accordance with the AAP Policy Statement for Visual System Assessment 
in Infants, Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American 
Academy of Pediatrics, 2016; located in the Study Operations Manual). Observations will be 
graded as normal or abnormal. Abnormal findings will be described. The red reflex should be 
normal (present and symmetrical for both eyes) at the screening/baseline visit.
7.2.3.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.) Any AE that occurs after the first dose of 
investigational product instillation will be considered a treatment-emergent AE (TEAE).


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Adverse events may also be determined by the investigator during study examinations as 
mentioned in previous sections.
7.2.3.5
Microbiology Laboratory Evaluations
All laboratory assays will be performed according to the laboratory’s normal procedures. 
All bioanalytical assays for the study will be validated following Food and Drug Administration 
(FDA)/International Conference on Harmonisation (ICH) guidelines, based on the method’s 
intended use. The lab will only receive sample identification numbers and collection dates, and 
the lab results will then be transferred to the central lab for data analysis. The lab will not receive 
any information on subject treatment assignment.
One swab sample from inferior conjunctival cul-de-sac of each eye will be collected at all study 
visits for all bacterial testing. An additional sample will be collected from each eye at Visit 1 for 
PCR testing of chlamydia and gonorrhea in subjects <2 months of age.  
Bacterial eradication as well as antibiotic sensitivity will be determined based on bacterial 
cultures using standard microbiological laboratory procedures. 
7.2.3.6
Pregnancy Test 
A urine pregnancy test is performed on all females of childbearing potential at Visits 1 and 5, or 
if pregnancy is suspected. Urine pregnancy test kits will be provided by the sponsor and read on 
site by qualified site personnel.
7.2.3.7
Health-related Quality of Life Assessments
Ocular discomfort associated with conjunctivitis symptoms will be assessed through the ocular 
discomfort scale (ODS). The ODS is composed of 3 items: pain, itching, and foreign body 
sensation. All items will be evaluated using a 0-10 scale. A separate scale will be administered 
for children younger than 8 years of age. Please see the Study operations manual for a detailed 
description of this assessment.


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, and Recording of Adverse 
Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event, including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.


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Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 


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data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine -hCG 
test or ultrasound result will determine the pregnancy onset date.
8.1.6
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category:

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: This includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol.)


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
Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a pre-specified total daily dose of 4 drops per eye of the product. 

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reported as a medication 
error.
The administration and/or use of an expired investigational product should be reported as a 
medication error.
In cases of overdose, the investigator should determine if the medical monitor must be contacted 
for consultation.
All investigational product provided to pediatric subjects should be administered or supervised
by the parent(s)/guardian/legally authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure, which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO/Shire medical monitor 
within 24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see 
Section 8.1.6) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the CRO/Shire medical monitor using the details specified in the emergency 
contact information section of the protocol.


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8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires in-subject hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in in subject 
hospitalization, or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject provides 
written informed consent (and assent, if applicable) until the defined follow-up period stated in 
Section 7.1.3 and must be reported to the Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 


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date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and/or the clinical CRO is responsible for notifying the relevant regulatory 
authorities and Institutional Review Boards (IRBs)/ethics committees (ECs) of related, 
unexpected SAEs.
In addition, the sponsor and/or the clinical CRO is responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the SHP640 
program. 
The investigator is responsible for notifying the local IRB, local EC, or relevant local regulatory 
authority of all SAEs that occur at his or her site as required.


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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigator’s authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the CRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRF Completion Guidelines. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unmask the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unmasking, any data that may unmask study team personnel 
will be presented as masked information or otherwise will not be made available. If applicable, 
unmasked data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be addressed.
In addition to a final SAP for the final analysis, a separate SAP for the interim analysis will be 
finalized prior to unmasking and performing the interim analysis. The SAP for the final analysis 


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will be finalized prior to unmasking of the study to preserve the integrity of the statistical 
analysis and study conclusions. 
All final statistical analyses will be performed after the database is locked and unmasked.
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513) Version 
9.2 or higher. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
An unmasked interim analysis (IA) will be performed after ~50% subjects exit the trial in the 
modified intent-to-treat (mITT) population (ie, n=252 in mITT), with data to be analyzed entered 
into the database, queried, and discrepancies resolved. The purpose of the IA will be to assess the 
adequacy of the initial sample size estimation by evaluating conditional power for the primary 
comparison of SHP640 versus placebo on clinical resolution in the treatment of subjects with 
bacterial conjunctivitis in the study eye at Visit 3 (Day 5). There is no intention to stop early for 
efficacy or futility based on the results from the IA. 
The IA will be performed by an external unmasked independent statistician and/or unmasked 
programmers based on a prespecified interim SAP. The interim SAP will explicitly describe how 
the conditional power is to be calculated and the precise rules for altering the sample size 
depending on the potential results. The interim SAP will be finalized prior to IA. The interim 
statistical report including the results will be distributed only to a limited group of people who 
are not involved in the conduct of the trial. All sponsor, CRO, and site staff involved in the 
conduct of the trial must remain masked throughout the trial. Recommendation from the IA to 
increase the sample size may require an amendment to the study protocol. No adjustment of type
I error rate is needed because the sole purpose of the planned IA is to adjust the sample size by 
using the conditional power approach, and the sample size will be changed only under certain 
conditions (Mehta and Pocock, 2011).
9.6
Sample Size Calculation and Power Considerations
The sample size was estimated for the primary comparison of SHP640 versus placebo on clinical 
resolution in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 
(Day 5) using nQuery Advisor 7.0. Subjects will be randomized 3:1:3 to receive either SHP640, 
PVP-I, or placebo within each age stratum. 
A sample size of 504 subjects (216 subjects in each of the SHP640 and placebo groups, 72 in 
PVP-I group) will ensure ~90% power to compare the SHP640 and placebo treatment groups 
assuming 61% and 45% subjects with clinical resolution, respectively, using Fisher’s Exact test 
at 2-sided 5% level of significance. All efficacy analyses will be based on the mITT with post-
baseline last observation carried forward for the subjects with missing clinical resolution status 
as Visit 3 (Day 5).
An exploratory PVP-I arm (ie, 72 subjects in mITT and approximately 103 randomized subjects) 
will be included in the trial to provide parameter estimates on PVP-I treatment effect to inform 
future studies. No formal hypothesis testing will be conducted on the PVP-I arm. 


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To ensure 504 subjects in the mITT population, approximately 721 subjects will be randomized 
in this study (approximately 309 subjects in each of SHP640 and placebo groups; approximately 
103 subjects in PVP-I group).
9.7
Study Population
The safety population will include all subjects who receive at least 1 dose of investigational 
product.
The intent-to-treat (ITT) population will include all randomized subjects. 
The mITT population consists of a subset of the ITT population who receive at least 1 dose of 
investigational product and have a positive bacterial culture (presence of 1 or more bacterial 
species at or above pathological threshold) at baseline in the study eye.
9.8
Efficacy Analyses
The analyses on primary, key secondary, secondary, and exploratory efficacy endpoints will be 
performed on the mITT population (unless specified otherwise) and will be presented by 
treatment group. 
Additional sensitivity analyses may be conducted in the ITT population.
For both efficacy and safety analyses, baseline is defined as the assessments taken prior to 
treatment at Visit 1 (Day 1).
9.8.1
Study Eye Designation
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a 
score of at least 1 for both ocular conjunctival discharge and bulbar conjunctival redness at 
baseline (baseline is defined as the assessments taken prior to treatment at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive bacterial culture (presence of 1 
or more bacterial species at or above pathological threshold) at baseline or both eyes eligible 
and both with a non-positive bacterial culture (absence of any bacterial species at or above 
pathological threshold) at baseline, the study eye will be the eye with the highest global 
clinical score (sum of bulbar conjunctival injection and ocular conjunctival discharge) at 
baseline. If both eyes have the same global clinical score at baseline, then the study eye will 
be the right eye. 

For subjects with both eyes eligible with a positive bacterial culture in 1 eye at baseline, the 
baseline bacterial culture positive eye will be the study eye. 

For subjects with only 1 eligible eye, the eligible eye will be the study eye irrespective of its 
baseline bacterial culture result. 
The study eye designation is summarized in the table below:


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Eligible Eye(s)
Bacterial Culture Results
Study Eye
Both eyes
Both eyes positive
Highest global clinical score at Visit 1 (Day 1)
(or right eye if scores are the same)
Both eyes
Both eyes negative
Highest global clinical score at Visit 1 (Day 1)
(or right eye if scores are the same)
Both eyes
One eye positive
The bacterial culture positive eye at Visit 1 (Day 1) 
One eye
Positive or negative for either eye
The eligible eye 
9.8.2
Primary Efficacy Endpoint
The primary efficacy endpoint is clinical resolution status (defined as absence [ie, a score of 0] 
of bulbar conjunctival injection and ocular conjunctival discharge) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo.
All efficacy analyses will be performed on the mITT population and presented by treatment 
groups. There is a single primary comparison for the single primary endpoint. Therefore, no 
adjustment of multiplicity is needed for the hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 5) will be 
compared between the SHP640 and placebo group. The comparison will be based on the 
proportion of subjects with clinical resolution in the study eye at Visit 3 (Day 5) using Fisher’s 
Exact test at 2-sided 0.05 significance level. 
If subjects have missing clinical resolution status at Visit 3 (Day 5), then the last post-baseline 
observation will be carried forward for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with 
clinical resolution in the study eye between SHP640 ophthalmic solution and placebo with the 
alternative of the non-zero difference in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 2-sided Fisher’s Exact 
test at 5% level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical 
method(s) including other methods of imputation of missing data. Sensitivity analyses may be 
conducted in the ITT population in addition to the mITT. In addition, descriptive statistics will 
be generated for the primary efficacy endpoint by treatment within the overall pediatric 
population (ie, birth to 18 years) and within each pediatric age stratum (<6 years and 6 to <18 
years) in mITT. A detailed plan for primary analysis including additional sensitivity analyses 
will be described in the SAP.
9.8.3
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoint is bacterial eradication status (defined as absence of all 
bacterial species present at or above pathological threshold at baseline) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo.


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All efficacy analyses will be performed on the mITT population and presented by treatment 
groups. In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary 
hypotheses will be tested sequentially. Each hypothesis will be tested using Fisher’s Exact test at 
2-sided 5.0% level with null hypothesis of no difference in the proportion of subjects for the 
endpoint between the 2 treatment groups. 
First, the primary efficacy endpoint will be tested. Only if the null hypothesis for the primary 
efficacy endpoint is rejected at 5.0% level, then the key secondary efficacy endpoint of bacterial 
eradication will be tested to compare the proportion of subjects with bacterial eradication 
between the SHP640 and placebo treatment group. If subjects have missing bacterial eradication 
status at Visit 3 (Day 5), then the last post-baseline observation will be carried forward for the 
determination of bacterial eradication of the study eye. 
Sensitivity analyses will also be done on key secondary efficacy endpoints using similar methods 
as described above. In addition, descriptive statistics will be generated for the key secondary 
efficacy endpoint by treatment within the overall pediatric population (ie, birth to 18 years) and 
within each pediatric age stratum (<6 years and 6 to <18 years) in the mITT. Details on the 
analyses will be described in the SAP.
9.8.4
Secondary Efficacy Endpoints
All secondary efficacy analyses will be performed on the mITT population and presented by 
treatment group. No hypothesis testing is planned for the secondary efficacy endpoints. All 
secondary efficacy endpoint will be summarized by treatment groups using descriptive statistics 
at each assessment visit. Continuous endpoints will be summarized by number of subjects (n), 
mean, median, standard deviation, minimum, maximum, and confidence intervals (CIs). Binary 
endpoints will be summarized by number of subjects (n), frequencies, proportions, and CIs. Time 
to event endpoint will be summarized by Kaplan-Meier survival estimates.
Secondary efficacy endpoints are defined as follows:

Clinical resolution status of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12) in the study eye

Bacterial eradication status (defined as absence of all bacterial species present at or above 
pathological threshold at baseline) as assessed by bacterial culture at Visits 2 (Day 3), 4 (Day 
8), and 5 (Day 12) in the study eye

Absolute and change from baseline of the individual clinical signs score (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12) in the study eye

The global clinical score (defined as the sum of bulbar conjunctival injection and ocular 
conjunctival discharge) and change from baseline in the global clinical score at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye


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
Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with 
neither injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8),
and 5 (Day 12) in the study eye

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8),
and 5 (Day 12) in the study eye

Use of rescue medication
9.8.5
Exploratory Efficacy Endpoints
The ocular discomfort endpoints will be evaluated by absolute and change from baseline of 
ocular discomfort scores (or by the binary ocular discomfort endpoint for children younger than 
8 years of age) due to conjunctivitis symptoms at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12). 
No hypothesis testing is planned for the exploratory efficacy endpoint. Exploratory endpoints 
will be summarized using methods similar to secondary endpoints.
9.9
Safety Analyses
Safety data will be presented for the safety population by treatment group and overall.
Safety data collected at baseline prior to treatment (Visit 1/Day 1) will be used as the baseline 
value for safety analysis.
Adverse events, including those suggestive of any local tolerability issues, will be coded using 
the Medical Dictionary for Regulatory Activities. The number of subjects and percentage with a 
TEAE as well as the number of TEAEs will be calculated overall, by system organ class, by 
preferred term, and by treatment group. Treatment-emergent adverse events will be further 
summarized by severity and relationship to investigational product. Adverse events related to 
investigational product, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized and listed.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or a 
non-ocular AE.
The following safety endpoints will be descriptively summarized by treatment group at each 
applicable visit:

BCVA

Slit lamp biomicroscopy

Lid 

Conjunctiva 

Cornea 


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
Anterior chamber 

Iris

Lens 

Non-dilated/dilated fundus examination

Vitreous 

Optic nerve 

Macula 

Urine pregnancy testing (for females of childbearing potential)
9.10
Other Analyses
No other analyses are planned in this study.


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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, European Union 
(EU) Directive 2001/20/EC and its updates, and local ethical and legal requirements.
In case of substantial amendment, approval from the Competent Regulatory Authority will be 
sought before implementation.
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC and its updates, as well as all applicable national and local laws and 
regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.


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10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study that has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC and its updates, and applicable regulatory requirements and 
guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 


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The coordinating principal investigator will be assigned and selected based on the extent of their 
involvement in the study and experience in the therapeutic area.
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs to ensure accurate and timely information is provided at all 
phases during the study may be done by the sponsor, applicable CRO, investigator, or, for 
multicenter studies, coordinating principal investigator according to national provisions and will 
be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data. All corrections to the eCRF must indicate the reason for 
change. If corrections are made after the review and signature by the investigator, he or she must 
be made aware of the change, and his or her awareness must be documented by re-signing the 
eCRF.   
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include but are not limited to the 
subject’s medical file, scales, ODS, and documented results of AdenoPlus test results.


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All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) will check the CRF 
entries against the source documents. The consent form includes a statement by which the
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
European Medicines Agency (EMA), United Kingdom Medicines and Healthcare products 
Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation, or honoraria; any proprietary interest in investigational product; and any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 


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translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to 
the objectives, potential benefits and risk, inconveniences, and subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent(s)/guardian/legally authorized representative/caregiver of the safe, responsible 
storage and administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form and assent form, 
where applicable, that was reviewed by the IRB/EC and received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 


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provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the CRO.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP640; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, other information (eg, initials and 
date of birth if the local law permits) may also be collected and used to assist the sponsor to 
verify the accuracy of the data (eg, to confirm that laboratory results have been assigned to the 
correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to 
and used in other countries that may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 


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commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.


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11.
REFERENCES
American Academy of Pediatrics 2016. Visual system assessment in infants, children, and young 
adults by pediatricians. Pediatrics, 137, 28-30.
Azari, A. A. & Barney, N. P. 2013. Conjunctivitis: a systematic review of diagnosis and 
treatment. Jama, 310, 1721-9.
Betadine 2004. Betadine Prescribing Information.
Capriotti, J. A., Stewart, K. P. & Pelletier, J. 2010. The unique challenges of viral conjunctivitis -
Its similarities to bacterial infection belie key differences that impact clinical care 
[Online]. Ophthalmology Management. Available: 
http://www.ophthalmologymanagement.com/articleviewer.aspx?articleid=104651.
CDC. 2010. Conjunctivitis (pink eye) [Online]. Centers for Disease Control and Prevention. 
Available: http://www.cdc.gov/conjunctivitis/clinical.html.
Chen, C. J. & Starr, C. E. 2008. Epidemiology of gram-negative conjunctivitis in neonatal 
intensive care unit patients. Am J Ophthalmol, 145, 966-970.e2.
Dias, C., Gonçalves, M. & João, A. 2013. Epidemiological study of hospital-acquired bacterial 
conjunctivitis in a level III neonatal unit. Sci World J, 1-5.
Donahue, S. P. & Baker, C. N. 2016. Procedures for the Evaluation of the Visual System by 
Pediatricians. Pediatrics, 137.
Ford, E., Nelson, K. E. & Warren, D. 1987. Epidemiology of epidemic keratoconjunctivitis. 
Epidemiol Rev, 9, 244-61.
Gordon, Y. J., Gordon, R. Y., Romanowski, E. & Araullo-Cruz, T. P. 1993. Prolonged recovery 
of desiccated adenoviral serotypes 5, 8, and 19 from plastic and metal surfaces in vitro. 
Ophthalmology, 100, 1835-9; discussion 1839-40.
Haas, J., Larson, E., Ross, B., See, B. & Saiman, L. 2005. Epidemiology and diagnosis of 
hospital-acquired conjunctivitis among neonatal intensive care unit patients. Pediatr 
Infect Dis J, 24, 586-589.
Maxidex 2007. Maxidex Prescribing Information.
Mehta, C. R. & Pocock, S. J. 2011. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Statistics in medicine, 30, 3267-84.
Nauheim, R. C., Romanowski, E. G., Araullo-Cruz, T., Kowalski, R. P., Turgeon, P. W., Stopak, 
S. S. & Gordon, Y. J. 1990. Prolonged recoverability of desiccated adenovirus type 19 
from various surfaces. Ophthalmology, 97, 1450-3.
O'Brien, T. P., Jeng, B. H., McDonald, M. & Raizman, M. B. 2009. Acute conjunctivitis: truth 
and misconceptions. Curr Med Res Opin, 25, 1953-61.
Patel, P. B., Diaz, M. C. G., Bennett, J. E. & Attia, M. W. 2007. Clinical features of bacterial 
conjunctivitis in children. Clin Investigations, 1-5.
Pelletier, J. S., Stewart, K., Trattler, W., Ritterband, D. C., Braverman, S., Samson, C. M., Liang, 
B. & Capriotti, J. A. 2009. A combination povidone-iodine 0.4%/dexamethasone 0.1% 
ophthalmic suspension in the treatment of adenoviral conjunctivitis. Adv Ther, 26, 776-
83.
Pelletier, M. R., Casella, L. G., Jones, J. W., Adams, M. D., Zurawski, D. V., Hazlett, K. R., Doi, 
Y. & Ernst, R. K. 2013. Unique structural modifications are present in the 
lipopolysaccharide from colistin-resistant strains of Acinetobacter baumannii. Antimicrob 
Agents Chemother, 57, 4831-40.


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Pocock, S. J. & Simon, R. 1975. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 31, 103-15.
Rours, I. G. I. J. G., Hammerschlag, M. R., Ott, A., De Faber, T. J. T. H. N., Verbrugh, H. A., de 
Groot, R. & Verkooyen, R. P. 2008. Chlamydia trachomatis as a cause of neonatal 
conjunctivitis in Dutch infants. Pediatrics, 121, e321.
Statham, M. O., Sharma, A. & Pane, A. R. 2008. Misdiagnosis of acute eye diseases by primary 
health care providers: incidence and implications. Med J Aust, 189, 402-4.
Visscher, K. L., Hutnik, C. M. & Thomas, M. 2009. Evidence-based treatment of acute infective 
conjunctivitis: Breaking the cycle of antibiotic prescribing. Can Fam Physician, 55,
1071-5.


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12.
APPENDICES




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Inclusion Criteria 3 was updated to remove lower age limit.
Inclusion Criteria 7 was expanded as follows:
Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better 
in each eye as measured using an Early Treatment Diabetic Retinopathy 
Study (ETDRS) chart. BCVA will be assessed by an age appropriate 
method in accordance with the AAP Policy Statement for Visual System 
Assessment in Infants, Children, and Young Adults by Pediatricians 
(Donahue and Baker 2016; American Academy of Pediatrics 2016). The 
policy statement recommends formal vision screening can begin at 3 years 
of age. VA measurements for children under the age of 3 will be done at 
the discretion of the investigator. If not done, child should be able to 
fixate on and follow a moving object, except subjects <2 months of age 
who have not yet developed this ability. Subjects <2 months will be 
enrolled at the discretion of Investigator.
Synopsis
Section 4.1
Exclusion criteria were modified and renumbered per the discretion of the 
study team prior to subject enrollment (the Exclusion Criteria numbers 
below reflect the current document unless noted otherwise):

Exclusion Criteria 11 and 12 were modified to reflect the 
removal of the lower age limit.

Exclusion Criteria 14 was added.

Exclusion Criteria 21 was modified as follows: Have used any 
topical ophthalmic steroids in the last ≤14 days.

Exclusion Criteria 24 was modified to note that use of hot or cold 
compresses is also not permitted during the study.
Synopsis
Section 4.2
It was clarified that time to event endpoint will be summarized by Kaplan-
Meier survival estimates.
Synopsis
Section 9.8.4
Noted that AE assessments will include local tolerability.
Synopsis
Section 9.9
Discontinuation language updated as follows:
A subject may withdraw from the study at any time for any reason without 
prejudice to their future medical care by the physician or at the institution. 
The investigator or sponsor may withdraw the subject at any time (eg, in 
the interest of subject safety). , there is no clinical improvement or 
worsening to an extent that it would be in the best interest of the subject to 
be treated with an alternate therapy for safety reasons).
Rescue treatment with a licensed antibiotic according to the local standard 
of care should be provided to subjects if, in the judgment of the 
investigator, there is no clinical improvement or worsening of their 
condition to an extent that it would be in the best interest of the subject to 
be treated with an alternate therapy for safety reasons. In such instances, 
the Investigational product should be discontinued, Visit 5 evaluations be 
performed at the time of subject discontinuation after which rescue 
treatment will be started. 
Section 4.4


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SHP640-303 Protocol Amendment 1
SHP640 (FST-100)
28 Nov 2016
The investigator is encouraged to discuss withdrawal of a subject from 
investigational product with the medical monitor when possible if 
necessary.
Table 2 “Common Excluded Treatments and Associated Washout 
Periods” was updated.
Section 5.2.2
Medical history will be classified as ocular (specified as left eye, right eye 
or both eyes) or non ocular by the investigator.
Section 7.2.1.2
Study sites will no longer follow pregnancies of the female partner of a 
male study participant.
Section 8.1.5
Section 8.1.5 “Clinical Laboratory and Other Safety Evaluations” was 
removed from the original protocol as these assessments are not a 
component of this study. Laboratory and other relevant assessments may
still be conducted in response to an AE and the PI can make a 
determination of medical significance based on the results.
Previous Section 8.1.5
It was noted that in case of substantial amendment, approval from the 
Competent Regulatory Authority will be sought before implementation.  
Section 10


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SHP640 (FST-100)
28 Nov 2016
APPENDIX 2     SCALES AND ASSESSMENTS
All scales assessments referenced in the protocol, including procedural instructions for the 
investigator, are in the Study Operations Manual and the Laboratory Manual (provided upon 
request).

Prot_000.pdf: 
PROTOCOL SHP640-303
TITLE:
A Phase 3, Multi-center, Randomized, Double-Masked Study to 
Evaluate the Clinical Efficacy and Safety of SHP640 (PVP-Iodine 0.6% 
and Dexamethasone 0.1%) Ophthalmic Suspension Compared to 
Placebo in the Treatment of Bacterial Conjunctivitis
DRUG:
SHP640
IND:
75,723
EUDRACT NO:
2016-003361-25
SPONSOR:
Shire
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 27 September 2016
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire




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Protocol SHP640-303
27 Sep 2016
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to the Shire Global Pharmacovigilance and Risk Management 
Department. Applicable fax numbers and e-mail address can be found on the form (sent under 
separate cover). A copy of this form must also be sent to the contract research organization 
(CRO)/Shire medical monitor by fax or e-mail using the details below.
Fax: 
Email: 
For protocol- or safety-related issues in the United States (US) and North American region, 
the investigator must contact the Shire medical monitor:
 MBBS, DPM, MS
Primary telephone number:
Fax: 
Alternate number: 
For protocol- or safety-related issues in regions other than North America, the investigator 
must contact the Quintiles 24/7 Emergency Contact center:
Primary telephone number: 
Alternate number:


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27 Sep 2016
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA),


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TABLE OF CONTENTS
1
BACKGROUND INFORMATION.......................................................................................20
1.1
Indication and Current Treatment Options...............................................................20
1.2
Product Background and Clinical Information ........................................................20
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................21
2.1
Rationale for the Study.............................................................................................21
2.2
Study Objectives ......................................................................................................21
2.2.1
Primary Objective..................................................................................................21
2.2.2
Key Secondary Objective ......................................................................................21
2.2.3
Secondary Objectives.............................................................................................21
2.2.4
Exploratory Objectives ..........................................................................................22
3
STUDY DESIGN ...................................................................................................................23
3.1
Study Design and Flow Chart ..................................................................................23
3.2
Duration and Study Completion Definition .............................................................23
3.3
Sites and Regions .....................................................................................................24
4
STUDY POPULATION.........................................................................................................25
4.1
Inclusion Criteria......................................................................................................25
4.2
Exclusion Criteria.....................................................................................................25
4.3
Reproductive Potential .............................................................................................27
4.3.1
Female Contraception............................................................................................27
4.4
Discontinuation of Subjects .....................................................................................28
4.4.1
Reasons for Discontinuation..................................................................................28
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................29
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................30
5.1
Prior Treatment ........................................................................................................30
5.2
Concomitant Treatment............................................................................................30
5.2.1
Permitted Treatment...............................................................................................30
5.2.2
Prohibited Treatment .............................................................................................30
6
INVESTIGATIONAL PRODUCT ........................................................................................32
6.1
Identity of Investigational Product...........................................................................32
6.1.1
Masking the Treatment Assignment ......................................................................32
6.1.2
Commercially Obtained Investigational Product...................................................32
6.2
Administration of Investigational Product(s)...........................................................32
6.2.1
Interactive Response Technology for Investigational Product Management ........32
6.2.2
Allocation of Subjects to Treatment ......................................................................32
6.2.3
Dosing....................................................................................................................33
6.2.4
Unmasking the Treatment Assignment..................................................................33
6.3
Labeling, Packaging, Storage, and Handling ...........................................................33


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6.3.1
Labeling .................................................................................................................33
6.3.2
Packaging...............................................................................................................34
6.3.3
Storage ...................................................................................................................34
6.3.4
Special Handling....................................................................................................35
6.4
Drug Accountability.................................................................................................35
6.5
Subject Compliance..................................................................................................36
7
STUDY PROCEDURES........................................................................................................37
7.1
Study Schedule.........................................................................................................37
7.1.1
Visit 1 (Day 1) .......................................................................................................37
7.1.2
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8) ............................................................39
7.1.3
Visit 5 (End of Study or Early Termination) .........................................................39
7.1.4
Additional Care of Subjects after the Study ..........................................................39
7.2
Study Evaluations and Procedures ...........................................................................39
7.2.1
Demographic and Other Baseline Characteristics .................................................39
7.2.1.1
Demographics.........................................................................................39
7.2.1.2
Medication and Medical History............................................................39
7.2.1.3
RPS AdenoPlus Test ..............................................................................40
7.2.2
Efficacy..................................................................................................................40
7.2.2.1
Clinical Resolution.................................................................................40
7.2.2.2
Bacterial Eradication..............................................................................40
7.2.3
Safety .....................................................................................................................41
7.2.3.1
Best Corrected Visual Acuity.................................................................41
7.2.3.2
Slit Lamp Biomicroscopy.......................................................................41
7.2.3.3
Non-dilated/Dilated Fundus Examination..............................................42
7.2.3.4
Adverse Event Collection.......................................................................42
7.2.3.5
Clinical Laboratory Evaluations.............................................................43
7.2.3.6
Pregnancy Test .......................................................................................43
7.2.3.7
Health-related Quality of Life Assessments...........................................43
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................44
8.1
Definition of Adverse Events, Period of Observation, and Recording of 
Adverse Events.........................................................................................................44
8.1.1
Severity Categorization..........................................................................................44
8.1.2
Relationship Categorization...................................................................................45
8.1.3
Outcome Categorization ........................................................................................45
8.1.4
Symptoms of the Disease Under Study .................................................................45
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................46
8.1.6
Pregnancy...............................................................................................................46
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................47


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8.2
Serious Adverse Event Procedures ..........................................................................47
8.2.1
Reference Safety Information................................................................................47
8.2.2
Reporting Procedures.............................................................................................48
8.2.3
Serious Adverse Event Definition .........................................................................48
8.2.4
Serious Adverse Event Collection Time Frame.....................................................49
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................49
8.2.6
Fatal Outcome........................................................................................................49
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................49
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................51
9.1
Data Collection.........................................................................................................51
9.2
Clinical Data Management.......................................................................................51
9.3
Data Handling Considerations..................................................................................51
9.4
Statistical Analysis Process......................................................................................51
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......52
9.6
Sample Size Calculation and Power Considerations................................................52
9.7
Study Population ......................................................................................................53
9.8
Efficacy Analyses.....................................................................................................53
9.8.1
Study Eye Designation...........................................................................................53
9.8.2
Primary Efficacy Endpoint ....................................................................................54
9.8.3
Key Secondary Efficacy Endpoints .......................................................................54
9.8.4
Secondary Efficacy Endpoints...............................................................................55
9.8.5
Exploratory Efficacy Endpoints.............................................................................56
9.9
Safety Analyses........................................................................................................56
9.10
Other Analyses .........................................................................................................57
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................58
10.1
Sponsor’s Responsibilities .......................................................................................58
10.1.1 Good Clinical Practice Compliance.......................................................................58
10.1.2 Indemnity/Liability and Insurance.........................................................................58
10.1.3 Public Posting of Study Information......................................................................58
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................58
10.1.5 Study Suspension, Termination, and Completion..................................................59
10.2
Investigator’s Responsibilities .................................................................................59
10.2.1 Good Clinical Practice Compliance.......................................................................59
10.2.2 Protocol Adherence and Investigator Agreement..................................................59
10.2.3 Documentation and Retention of Records.............................................................60
10.2.3.1
Case Report Forms.................................................................................60


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10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................60
10.2.3.3
Audit/Inspection.....................................................................................61
10.2.3.4
Financial Disclosure...............................................................................61
10.3
Ethical Considerations..............................................................................................61
10.3.1 Informed Consent...................................................................................................61
10.3.2 Institutional Review Board or Ethics Committee..................................................62
10.4
Privacy and Confidentiality......................................................................................62
10.5
Study Results/Publication Policy .............................................................................63
11 REFERENCES .......................................................................................................................65
12 APPENDICES ........................................................................................................................67


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LIST OF TABLES
Table 1
Schedule of Assessments .........................................................................................18
Table 2 Common Excluded Treatments and Associated Washout Periods ..........................31
LIST OF FIGURES
Figure 1 SHP640-303 Study Design.......................................................................................23
LIST OF APPENDICES
Appendix 1
Protocol History .....................................................................................68
Appendix 2
Scales and Assessments .........................................................................69


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LIST OF ABBREVIATIONS
AAP
American Academy of Pediatrics
AE
adverse event
BCVA
best corrected visual acuity
CFU
colony-forming unit
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
EC
ethics committee
eCRF
electronic case report form
EMA
European Medicines Agency
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
IA
interim analysis
ICH
International Conference on Harmonisation
IMP
investigational medicinal product
IOP
intraocular pressure
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
mITT
modified intent-to-treat
MRSA
methicillin-resistant Staphylococcus aureus
NCS
not clinically significant
NF
National Formulary
ODS
ocular discomfort scale
PVP-I
povidone-iodine


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QID
4 times a day
RPS
Rapid Pathogen Screening, Inc.
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment-emergent adverse event
US
United States
USP
United States Pharmacopeia
VA
visual acuity
VBR
Validated Bulbar Redness


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STUDY SYNOPSIS
Protocol number: SHP640-303
Drug: SHP640
Title of the study: A Phase 3, Multi-center, Randomized, Double-Masked Study to Evaluate the Clinical Efficacy 
and Safety of SHP640 (PVP-Iodine 0.6% and Dexamethasone 0.1%) Ophthalmic Suspension Compared to Placebo 
in the Treatment of Bacterial Conjunctivitis
Number of subjects (total and for each treatment arm):
Total subjects: Approximately 721
SHP640 treatment arm: Approximately 309
Povidone-iodine (PVP-I) treatment arm: Approximately 103
Placebo treatment arm: Approximately 309 
Investigator(s): multicenter study
Site(s) and Region(s): 
The study will be conducted in approximately 90 sites across North America, South America, Asia/Pacific, and 
Europe.
Study period (planned):
December 2016 to March 2018
Clinical phase:
3
Objectives:
Primary:
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical resolution (defined as 
absence of bulbar conjunctival injection and ocular conjunctival discharge) compared with placebo in the treatment 
of subjects with bacterial conjunctivitis in the study eye at Visit 3 (Day 5). 
Secondary:
The key secondary objective of this study is to evaluate the efficacy of SHP640 based on bacterial eradication 
(defined as absence of all bacterial species present at or above pathological threshold at baseline in the study eye) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 (Day 5).
Secondary objectives of this study are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints:

Clinical resolution of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12)

Bacterial eradication at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12)

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival injection and ocular 
conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

The global clinical score (sum of bulbar conjunctival injection and ocular conjunctival discharge) and change 
from baseline in the global clinical score at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12)

Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither injection nor 
discharge having a score of 2 at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the treatment of subjects 
with bacterial conjunctivitis


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Rationale:
The clinical presentation of conjunctivitis is often nonspecific, and differential diagnosis of different types of 
conjunctivitis can be challenging (Azari and Barney 2013; O’Brien et al. 2009). Diagnostic testing to differentiate 
the underlying cause of infection is rarely performed in a clinical setting; misdiagnosis can occur in up to 50% of 
cases, which often results in improper antibiotic treatment (Visscher et al. 2009). Incorrect treatment can not only 
increase healthcare costs from unnecessary antibiotic prescriptions and repeat office visits but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or methicillin-resistant Staphylococcus 
aureus). In addition, there is also a risk of overuse and misuse of antibiotics, which are ineffective in the treatment 
of viral infections (Statham et al. 2008). An unmet medical need therefore exists for a safe and efficacious treatment 
that addresses both bacterial and adenoviral conjunctivitis, 2 of the leading causes of acute infectious conjunctivitis. 
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, with 
dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious and inflammatory 
components of adenoviral and bacterial conjunctivitis.
Investigational product, dose, and mode of administration:
The drug product is SHP640 (0.1% dexamethasone and 0.6% PVP-I) ophthalmic suspension.
The comparators are placebo ophthalmic solution and 0.6% PVP-I ophthalmic solution.
Subjects will instill 1 drop of investigational product in each eye 4 times daily (with a minimum of 2 hours between 
doses) for 7 days.
Methodology:
Once screening and baseline assessments are complete and subjects are confirmed eligible to enroll in the study, 
subjects will be randomized, and investigational product will be administered on the same day (Day 1). The first 
dose will be administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a 
day for 7 days. Additional visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). The study 
will last up to 13 days. 
Inclusion and exclusion criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions (by the 
parent(s), guardian, or legally authorized representative, if applicable).
2.
Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), guardian, or legally   
authorized representative(s) informed consent (and assent, if applicable) to participate in the study.
3.
Be ≥1 month of age at Visit 1.
4.
Have a negative AdenoPlus® test in both eyes within 24 hours of Visit 1 or at Visit 1.
5.
Have a clinical diagnosis of suspected bacterial conjunctivitis in at least 1 eye confirmed by the presence of the 
following minimal clinical signs and symptoms in that same eye:

Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤3 days prior to Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection Scale

Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival Discharge Scale
6.
Be willing to discontinue contact lens wear for the duration of the study.
7.
Have a best corrected visual acuity (BCVA) of 0.60 logMAR or better in each eye as measured using an Early 
Treatment Diabetic Retinopathy Study chart. BCVA will be assessed by an age-appropriate method. 
Every attempt should be made to obtain a BCVA measurement in children, and if it is unobtainable, the 
decision as to whether the criterion is met will be at the investigator’s discretion. 
8.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 


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requirements of the protocol or females of non-childbearing potential.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Current or recurrent disease that could affect the action, absorption, or disposition of the investigational product, 
or clinical or laboratory assessments, per investigator’s discretion.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may make the subject 
unlikely to fully complete the study, or any condition that presents undue risk from the investigational product 
or procedures.
3.
Have known or suspected intolerance or hypersensitivity to the investigational product, closely related 
compounds, or any of the stated ingredients. 
4.
Prior enrollment in a FST-100 or SHP640 clinical study.
5.
Subjects who are employees, or immediate family members of employees (who are directly related to study 
conduct), at the investigational site.
6.
Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned for the period of the 
study.
7.
Have a preplanned overnight hospitalization during the period of the study.
8.
Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, iritis, ulcerative 
keratitis, chronic blepharoconjunctivitis), other than bacterial conjunctivitis.
9.
Have active or a history of ocular herpes.
10. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with the diagnosis of 
ocular allergy, toxic conjunctivitis, or non-bacterial ocular infection (eg, viral, fungal, acanthamoebal, other 
parasitic).
11. Infants (ie, subjects between 1 month and 12 months of age) who have suspected or confirmed ophthalmia 
neonatorum of gonococcal, chlamydia, herpetic, or chemical origin.
12. Infants (ie, subjects between 1 month and 12 months of age) whose birth mothers had any sexually transmitted 
disease within 1 month of delivery.
13. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
14. Be a known intraocular pressure (IOP) steroid responder, have a known history of glaucoma, be a glaucoma 
suspect, or have a known history of an elevated IOP >21 mmHg.
15. Have any known clinically significant optic nerve defects. 
16. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to previous corneal trauma or 
dry eye syndrome; presence of corneal epithelial defect or any significant corneal opacity at Visit 1.
17. Presence of significant, active condition in the posterior segment that requires invasive treatment (eg, 
intravitreal treatment with vascular endothelial growth factor inhibitors or corticosteroids) and may progress 
during the study participation period. 
18. Have used any topical ocular or systemic antibiotics within ≤7 days of enrollment. 
19. Have used any topical ocular non-steroidal anti-inflammatory drugs within ≤1 day of enrollment.
20. Have used any topical ophthalmic steroids in the last ≤30 days.
21. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 days prior to 
enrollment) use of inhaled and nasal corticosteroids is allowed, given no anticipated change in dose for the 
duration of the study. Topical dermal steroids are allowed except in the periocular area.
22. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
23. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter preparations such 


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Protocol SHP640-303
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as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all topical ophthalmic products for the 
duration of the study.
24. Have any significant ocular disease (eg, Sjogren’s syndrome) or any uncontrolled systemic disease or 
debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted diseases/infections, diabetes,
or cystic fibrosis) that may affect the study parameters, per investigator’s discretion.
25. Any known history of immunodeficiency disorder or known active conditions predisposing to 
immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of active hepatitis A 
(anti-hepatitis A virus immunoglobulin M), or organ or bone marrow transplantation.
26. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s opinion, may 
impact this Shire-sponsored study.
Maximum duration of subject involvement in the study:
Subject participation will last up to 13 days.
Screening, randomization, and the first treatment administration will occur at Visit 1 (Day 1). 
Additional visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). 
All follow-up procedures will be conducted at Visit 5 (Day 12).
Endpoints and statistical analysis:
Primary Efficacy Endpoint:
Clinical resolution status (defined as absence of bulbar conjunctival injection and ocular conjunctival discharge) in 
the study eye at Visit 3 (Day 5) between SHP640 and placebo.
Key Secondary Efficacy Endpoints:
Bacterial eradication status (defined as absence of all bacterial species present at or above pathological threshold at 
baseline) in the study eye at Visit 3 (Day 5) between SHP640 and placebo.
Secondary Efficacy Endpoints:

Clinical resolution status of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) in the study 
eye

Bacterial eradication status (defined as absence of all bacterial species present at or above pathological 
threshold at baseline in the study eye) as assessed by bacterial culture at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 
12) in the study eye 

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival injection and ocular 
conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye 

The global clinical score (defined as the sum of bulbar conjunctival injection and ocular conjunctival discharge) 
and change from baseline in the global clinical score at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in 
the study eye 

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12) in the study eye 

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with neither injection nor 
discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye 

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in 
the study eye 
Safety Endpoints:


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
BCVA

Slit lamp biomicroscopy 

Non-dilated/dilated fundus examination

Urine pregnancy testing (for females of childbearing potential)

Adverse events (AEs)
Statistical Methods:
The analyses on primary, key secondary, secondary, and exploratory efficacy endpoints will be performed on the 
modified intent-to-treat (mITT) population. Additional sensitivity analyses may be conducted on the intent-to-treat 
(ITT) population. Safety analyses will be conducted on the safety population.
For both efficacy and safety analyses, baseline is defined as the assessments taken prior to treatment at Visit 1 (Day 
1).
Analysis Populations:
The safety population will include all subjects who receive at least 1 dose of investigational product.
The ITT population will include all randomized subjects. 
The mITT population consists of a subset of the ITT population who receive at least 1 dose of investigational 
product and have a positive bacterial culture (presence of 1 or more bacterial species at or above pathological 
threshold) at baseline in the study eye.
Designation of Study Eye:
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a score of at least 1 for 
both ocular  conjunctival discharge and bulbar conjunctival redness at baseline (baseline is defined as the 
assessments taken prior to treatment at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive bacterial culture (presence of 1 or more bacterial 
species at or above pathological threshold) at baseline or both eyes eligible and both with a non-positive 
bacterial culture (absence of any bacterial species at or above pathological threshold) at baseline, the study eye 
will be the eye with the highest global clinical score (sum of bulbar conjunctival injection and ocular 
conjunctival discharge) at baseline. If both eyes have the same global clinical score at baseline, then the study 
eye will be the right eye.

For subjects with both eyes eligible with a positive bacterial culture in one eye at baseline, the baseline bacterial 
culture positive eye will be the study eye.

For subjects with only 1 eligible eye, the eligible eye will be the study eye irrespective of its baseline bacterial 
culture status.
Primary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. There is a single primary 
comparison for the single primary endpoint. Therefore, no adjustment of multiplicity is needed for the hypothesis 
testing for the primary objective.
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 5) will be compared between the 
SHP640 and placebo group. The comparison will be based on the proportion of subjects with clinical resolution in 
the study eye at Visit 3 (Day 5) using Fisher’s Exact test at 2-sided 0.05 significance level.
If subjects have missing clinical resolution status at Visit 3 (Day 5), then the last post-baseline observation will be 
carried forward for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with clinical resolution in the 
study eye between SHP640 ophthalmic Solution and placebo with the alternative of the non-zero difference in the 
proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 2-sided Fisher’s Exact test at 5% level of 


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significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical method(s) including 
methods of imputation of missing data. Sensitivity analyses may be conducted in the ITT in addition to the mITT.
Key Secondary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. The key secondary efficacy 
endpoint of this study is bacterial eradication status in the study eye at Visit 3 (Day 5) between SHP640 and placebo. 
In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary hypotheses will be tested 
sequentially. Each hypothesis will be tested using Fisher’s Exact test at 2-sided 5.0% level with null hypothesis of 
no difference in the proportion of subjects for the endpoint between the 2 treatment groups. 
First, the primary efficacy endpoint will be tested. Only if the null hypothesis for the primary efficacy endpoint is 
rejected at 5.0% level, then the key secondary efficacy endpoint of bacterial eradication will be tested to compare 
the proportion of subjects with bacterial eradication between the SHP640 and placebo treatment group. If subjects 
have missing bacterial eradication at Visit 3 (Day 5), then the last post-baseline observation will be carried forward 
for the determination of bacterial eradication of the study eye. 
Sensitivity analyses will also be done on the key secondary efficacy endpoint using similar methods as described 
above.
Secondary Efficacy Analyses:
No hypothesis testing is planned for the secondary efficacy endpoints. All secondary efficacy endpoints will be 
summarized by treatment groups using descriptive statistics at each assessment visit. Continuous endpoints will be 
summarized by number of subjects (n), mean, median, standard deviation, minimum, maximum, and confidence 
intervals (CIs). Binary endpoints will be summarized by number of subjects (n), frequencies, proportions, and CIs.
Safety Analyses:
Safety data will be presented for the safety population by treatment group and overall.
Safety data collected at baseline prior to treatment (Visit 1/Day 1) will be used as the baseline value for safety 
analysis.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The number of subjects and 
percentage with a treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated 
overall, by system organ class, by preferred term, and by treatment group and overall. TEAEs will be further 
summarized by severity and relationship to investigational product. AEs related to investigational product, AEs 
leading to withdrawal, serious AEs, and deaths will be similarly summarized and listed. Any AE that occurs after the 
first dose of investigational product instillation will be considered a TEAE.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or a non-ocular AE.
Slit lamp biomicroscopy, non-dilated/dilated fundus exam, BCVA, and urine pregnancy test (for females of 
childbearing potential) will be descriptively summarized by treatment group and overall at each applicable visit.


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Study Schedule
Table 1
Schedule of Assessments
Procedure
(All ocular assessments and procedures 
performed bilaterally)
Visit 1
Screeninga and Baseline
(Day 1)
-1 Day
Visit 2
(Day 3)
Visit 3
(Day 5)
Visit 4
(Day 8)
Visit 5b
(Day 12)
+1 Day
Informed consent/assenta
X
Inclusion/exclusion criteriaa
X
Medical history 
X
Demographics
X
Concomitant medications
X
X
X
X
X
Urine pregnancy test
Xc
Xc
Ocular discomfort scale
X
X
X
X
X
Best corrected visual acuity
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
Bulbar conjunctival injection evaluation
X
X
X
X
X
Ocular conjunctival discharge evaluation
X
X
X
X
X
RPS AdenoPlus® test
Xd
Conjunctival swab for bacterial culturee
X
Xf
Xf
Xf
X
Non-dilated/dilated fundus examinationk
X
X
Randomizationg
X
Dispense investigational producth
X
Instill medication
Xh
Xi
Xi
Collect investigational product
X
Xb
Compliance assessment
X
X
X
Xb
Drug accountability
X
Xb
Adverse events
Xj
X
X
X
X
Study completion
X


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Table 1
Schedule of Assessments
Procedure
(All ocular assessments and procedures 
performed bilaterally)
Visit 1
Screeninga and Baseline
(Day 1)
-1 Day
Visit 2
(Day 3)
Visit 3
(Day 5)
Visit 4
(Day 8)
Visit 5b
(Day 12)
+1 Day
ET=early termination; RPS=Rapid Pathogen Screening, Inc.
a Informed consent and confirmation of inclusion/exclusion criteria can be conducted on Day -1; these criteria must be reconfirmed on Day 1.
b If investigational product is discontinued, regardless of the reason, all discontinued subjects should proceed to Visit 5 whenever possible. Subjects who
discontinue the study and proceed to Visit 5 should perform all Visit 5 assessments as well as drug return, compliance, and accountability.
c Women of childbearing potential, prior to enrollment and at exit from the study
d One swab sample from inferior conjunctival cul-de-sac of each eye will be collected for all bacterial testing. 
e Conjunctival swab samples MUST be taken at least 12 hours after the last dose of investigational product at Visits 2, 3, 4, and ET, if applicable.
f If not previously conducted within 24 hours of Visit 1 (Day 1)
g All assessments, randomization, and medication instillation on Day 1 must take place with sufficient time to allow all 4 Day 1 doses (with a minimum of 2 
hours between doses).
h The investigational product bottle should be shaken well prior to use at each dosing. The first dose will be administered by site staff on Day 1, and thereafter 
subjects will administer 1 drop in each eye 4 times a day for 7 days.
i Medication instillation should only be performed in-office if it is necessary.
j Monitoring for adverse events will begin after informed consent is obtained.
k If a non-dilated fundus exam is not feasible, a dilated examination should be conducted. For each subject, the exam should be conducted the same way (either 
non-dilated or dilated) at both Visits 1 and 5 (or ET). 


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1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Conjunctivitis affects all populations worldwide of all ages and social strata, irrespective of 
gender. Infectious conjunctivitis (adenoviral and bacterial) represents a serious public health 
issue due to a risk of highly infectious epidemics, lost productivity, significant subject 
discomfort, and, in some cases, permanent visual compromise from long-term, immune-mediated 
sequelae (Capriotti et al. 2010; Ford et al. 1987; Gordon et al. 1993; Nauheim et al. 1990;
Pelletier et al. 2009). Bacterial conjunctivitis is the second-most common cause of infectious 
conjunctivitis with a viral etiology being the most common cause (Azari and Barney 2013). 
Bacterial etiology is more common in children, potentially accounting for 50-75% of all 
infectious conjunctivitis cases occurring in children (Azari and Barney 2013). The condition is 
caused by a wide variety of bacteria, including gram-positive species such as Staphylococcus 
aureus and Streptococcus pneumoniae and gram-negative species such as Haemophilus 
influenzae, Chlamydia trachomatis, and Moraxella catarrhalis (Azari and Barney 2013; Chen 
and Starr 2008; CDC 2010; Dias et al. 2013; Haas et al. 2005; Patel et al. 2007; Rours et al. 
2008). Bacterial conjunctivitis typically lasts for 7 to 10 days, yet, in the absence of adequate 
treatment, it can last for weeks or months.
1.2
Product Background and Clinical Information
SHP640, a novel topical ophthalmic suspension, is currently under development for the treatment 
of infectious conjunctivitis (adenoviral and bacterial).
SHP640 contains 2 active ingredients: povidone-iodine (PVP-I) and dexamethasone. PVP-I is a 
multivalent broad-spectrum local antiseptic with bactericidal and fungicidal properties. The 
effect on vegetative cells of various bacteria and fungi is due to the liberation of free iodine from 
the complex. It is effective against many viruses, protozoa, yeasts, cysts, and spores 
(Mundipharma AG 2004). Dexamethasone is a corticosteroid routinely used as a topical 
ophthalmic suspension for the treatment of ocular inflammation. It suppresses the inflammatory 
response to a variety of causes of inflammation (Novartis 2007). Both components are currently 
approved for use in other indications (at similar or higher concentrations) and have been shown 
to be safe and efficacious for use on the ocular surface in humans. The combination of PVP-I and 
dexamethasone has been shown to rapidly kill common ocular pathogens, including viruses, 
gram-positive bacteria (including methicillin-resistant Staphylococcus aureus [MRSA]), and 
gram-negative bacteria (Pelletier et al. 2013).
Always refer to the latest version of the SHP640 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy, and safety of SHP640. 


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2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The clinical presentation of conjunctivitis is often nonspecific, and differential diagnosis of 
different types of conjunctivitis can be challenging (Azari and Barney 2013; O'Brien et al. 2009). 
Diagnostic testing to differentiate the underlying cause of infection is rarely performed in a 
clinical setting; misdiagnosis can occur in up to 50% of cases, which often results in improper 
antibiotic treatment (Visscher et al. 2009). Incorrect treatment can not only increase healthcare 
costs from unnecessary antibiotic prescriptions and repeat office visits, but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or MRSA). In 
addition, there is also a risk of overuse and misuse of antibiotics, which are ineffective in the 
treatment of viral infections (Statham et al. 2008). An unmet medical need therefore exists for a 
safe and efficacious treatment that addresses both bacterial and adenoviral conjunctivitis, 2 of the 
leading causes of acute infectious conjunctivitis.
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, 
with dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious 
and inflammatory components of adenoviral and bacterial conjunctivitis.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical 
resolution (defined as absence of bulbar conjunctival injection and ocular conjunctival discharge) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye 
at Visit 3 (Day 5). 
2.2.2
Key Secondary Objective
The key secondary objective is to evaluate the efficacy of SHP640 based on bacterial eradication 
(defined as absence of all bacterial species present at or above pathological threshold at baseline 
in the study eye) compared with placebo in the treatment of subjects with bacterial conjunctivitis 
in the study eye at Visit 3 (Day 5).
2.2.3
Secondary Objectives
The secondary objectives are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints: 

Clinical resolution of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12)

Bacterial eradication at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12) 

Absolute and change from baseline of the individual clinical signs (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12)


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
The global clinical score (sum of bulbar conjunctival injection and ocular conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 5), 4 (Day 8), and 5 (Day 12) 

Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) 

Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither 
injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12) 

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12) 

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the 
treatment of subjects with bacterial conjunctivitis
2.2.4
Exploratory Objectives
The exploratory objectives of this study are as follows: 

To evaluate ocular discomfort due to conjunctivitis symptoms in subjects receiving SHP640 
compared to PVP-I and placebo at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)


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3
STUDY DESIGN
3.1
Study Design and Flow Chart
SHP640-303 is a global, multicenter, randomized, double-masked, parallel-group, placebo-
controlled study designed to demonstrate the safety and efficacy of SHP640 ophthalmic 
suspension compared to placebo in treating bacterial conjunctivitis. In addition, an exploratory 
arm of PVP-I 0.6% ophthalmic solution will be included.
Approximately 721 subjects ≥1 month of age will be randomized into the study at Visit 1 
(Day 1). Randomization will be stratified by age to maintain the randomization ratio among 
subjects 1 month to <6 years, 6 to <18 years, and subjects ≥18 years. Subjects will be 
randomized 3:1:3 to receive either SHP640, PVP-I, or placebo within each stratum. 
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced randomization will be used in this study to 
maintain the randomization ratio within each stratum. 
Once screening and baseline assessments are complete and subjects are confirmed eligible to 
enroll in the study, subjects will be randomized, and investigational product will be administered 
on the same day (Day 1). The first dose will be administered by site staff on Day 1, and 
thereafter subjects will administer 1 drop in each eye 4 times a day (QID) for 7 days. Additional 
visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). All follow-up 
procedures will be conducted at Visit 5 (Day 12). The study will last up to 13 days. 
Figure 1 provides the study design.
Figure 1
SHP640-303 Study Design
PVP-I=povidone iodine
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 13 days. The 
study will be completed in approximately 1.5 years. 


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The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit (Visit 5) 
or contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
The study will be conducted in approximately 90 sites across North America, South America, 
Asia/Pacific, and Europe.


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4
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed. If a subject is younger 
than the legal age of consent (per local laws), the subject’s parent(s), guardian, or legally 
authorized representative will provide written informed consent; the subject will provide verbal 
or written assent as appropriate.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions (by the parent(s), guardian, or legally authorized representative, if applicable).
2. Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), 
guardian, or legally authorized representative(s) informed consent (and assent, if applicable) 
to participate in the study.
3. Be ≥1 month of age at Visit 1.
4. Have a negative AdenoPlus® test in both eyes within 24 hours of Visit 1 or at Visit 1.
5. Have a clinical diagnosis of suspected bacterial conjunctivitis in at least 1 eye confirmed by 
the presence of the following minimal clinical signs and symptoms in that same eye:

Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤3 days prior to 
Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection 
Scale

Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
6. Be willing to discontinue contact lens wear for the duration of the study.
7. Have a best corrected visual acuity (BCVA) of 0.60 logMAR or better in each eye as 
measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will 
be assessed by an age-appropriate method. Every attempt should be made to obtain a BCVA 
measurement in children, and if it is unobtainable, the decision as to whether the criterion is 
met will be at the investigator’s discretion. 
8. Male, or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Current or recurrent disease that could affect the action, absorption, or disposition of the 
investigational product, or clinical or laboratory assessments, per investigator’s discretion.


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2. Current or relevant history of physical or psychiatric illness, any medical disorder that may
make the subject unlikely to fully complete the study, or any condition that presents undue 
risk from the investigational product or procedures.
3. Have known or suspected intolerance or hypersensitivity to the investigational product, 
closely related compounds, or any of the stated ingredients. 
4. Prior enrollment in a FST-100 or SHP640 clinical study.
5. Subjects who are employees, or immediate family members of employees (who are directly 
related to study conduct), at the investigational site.
6. Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned 
for the period of the study.
7. Have a preplanned overnight hospitalization during the period of the study.
8. Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, 
iritis, ulcerative keratitis, chronic blepharoconjunctivitis), other than bacterial conjunctivitis.
9. Have active or a history of ocular herpes.
10. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with 
the diagnosis of ocular allergy, toxic conjunctivitis, or non-bacterial ocular infection (eg, 
viral, fungal, acanthamoebal, other parasitic). 
11. Infants (ie, subjects between 1 month and 12 months of age) who have suspected or 
confirmed ophthalmia neonatorum of gonococcal, chlamydia, herpetic or chemical origin.
12. Infants (ie, subjects between 1 month and 12 months of age) whose birth mothers had any 
sexually transmitted disease within 1 month of delivery.
13. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
14. Be a known intraocular pressure (IOP) steroid responder, have a known history of glaucoma, 
be a glaucoma suspect, or have a known history of an elevated IOP >21 mmHg.
15. Have any known clinically significant optic nerve defects. 
16. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to 
previous corneal trauma or dry eye syndrome; presence of corneal epithelial defect or any 
significant corneal opacity at Visit 1.
17. Presence of significant, active condition in the posterior segment that requires invasive 
treatment (eg, intravitreal treatment with vascular endothelial growth factor inhibitors or 
corticosteroids) and may progress during the study participation period. 
18. Have used any topical ocular or systemic antibiotics within ≤7 days of enrollment. 
19. Have used any topical ocular non-steroidal anti-inflammatory drugs within ≤1 day of 
enrollment.
20. Have used any topical ophthalmic steroids in the last ≤30 days.
21. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 
days prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no 


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anticipated change in dose for the duration of the study. Topical dermal steroids are allowed 
except in the periocular area.
22. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
23. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all 
topical ophthalmic products for the duration of the study.
24. Have any significant ocular disease (eg, Sjogren’s syndrome) or any uncontrolled systemic 
disease or debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted 
diseases/infections, diabetes, or cystic fibrosis) that may affect the study parameters, per 
investigator’s discretion.
25. Any known history of immunodeficiency disorder or known active conditions predisposing 
to immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of  
active hepatitis A (anti-hepatitis A virus immunoglobulin M), or organ or bone marrow 
transplantation.
26. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study.
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception throughout the study period. If hormonal contraceptives are used, they should be 
administered according to the package insert. Females of childbearing potential who are not 
currently sexually active must agree to use acceptable contraception, as defined below, if they 
become sexually active during the period of the study.
Female children and adolescent subjects should be either:

Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine pregnancy test at Visit 1. Females of 
childbearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Adult female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and ≥age 51 years)

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or


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
Females of childbearing potential with a negative urine pregnancy test at Visit 1 and prior to 
randomization. Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use acceptable methods of contraception. 
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Intrauterine hormone-releasing systems plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam) 

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the screening visit (Visit 1), plus condoms. 
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, if in the judgment of the investigator, there is no clinical 
improvement or worsening to an extent that it would be in the best interest of the subject to be 
treated with an alternate therapy for safety reasons). The investigator is encouraged to discuss 
withdrawal of a subject from investigational product with the medical monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Visit 5 are to be performed as completely as possible. Whenever possible, all discontinued 
subjects should also undergo the protocol-specified follow-up (proceed to Visit 5). Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded in the source 
documents. The reason for termination and the date of stopping investigational product must be 
recorded in the case report form (CRF) and source documents.
Subject numbers for subjects who discontinue will not be reused. 
4.4.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF. 
Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol deviation

Withdrawal by subject

Lost to follow-up


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
Lack of efficacy

Physician decision

Study terminated by sponsor

Withdrawal by parent(s)/guardian/legally authorized representative (if applicable)

Other  (If “Other” is selected, the investigator must specify on the CRF.)
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.


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5
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment received within 30 days prior to the screening visit (Visit 1; or 
pharmacokinetic equivalent of 5 half-lives, whichever is longer) and through the final study 
contact (including protocol-defined follow-up period) must be recorded on the appropriate CRF 
page.
5.1
Prior Treatment
Prior treatment includes all treatment received within 30 days prior to the screening visit 
(Visit 1) (or pharmacokinetic equivalent of 5 half-lives, whichever is longer). Prior treatment 
information must be recorded on the appropriate CRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment other than the investigational production taken 
between the dates of the first dose of investigational product and the end of Visit 5 (the end of 
study visit), inclusive. Concomitant treatment information must be recorded on the appropriate 
CRF page.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
Medications not indicated as prohibited are permitted, including treatments for general 
non-excluded medical conditions.
In the event of an emergency, any needed medications may be prescribed without prior approval, 
but the medical monitor must be notified of the use of any prohibited medications immediately 
thereafter.
5.2.2
Prohibited Treatment
Table 2 details the washout period for common prior treatments that are excluded medications 
for this study. 


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Table 2
Common Excluded Treatments and Associated Washout Periods
Minimum Time Prior to First Dose
Notes
Treatment
30 days 
14 days
7 days
1 day
2 hours
Topical ocular NSAIDs
X
Topical ocular or systemic antivirals
X
Topical ophthalmic steroids
X
Systemic corticosteroid agents
X
Stable use of inhaled or nasal 
corticosteroids
X
Allowed ≥30 days if 
no anticipated dose 
changes during the 
study
Noncorticosteroid immunosuppressive 
agents
X
Topical ophthalmic solutions, 
including tear substitutes, and OTC 
preparations (ie, lid scrubs)
X
Must be able to 
discontinue use for 
the duration of the 
study
NSAID=non-steroidal anti-inflammatory drug; OTC=over-the-counter
Treatments not listed in Table 2 are considered permitted. 


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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
Three test products will be used in the clinical development program. The drug product is 
SHP640 (0.1% dexamethasone and 0.6% PVP-I) ophthalmic suspension, the comparator is 0.6% 
PVP-I ophthalmic solution, and the placebo product is placebo ophthalmic solution. Each of 
these test products are manufactured aseptically and filled in sterile plastic ophthalmic bottles. 
The placebo contains 2 additional ingredients relative to the others: benzalkonium chloride, 
United States Pharmacopeia (USP), EP, used as a preservative, and caramel color, National 
Formulary (NF), included to match the dark brown color of the PVP-I active ingredient. 
Additional information on the 3 test products is provided in the current SHP640 investigator’s 
brochure.
6.1.1
Masking the Treatment Assignment
The packaging, appearance, and labeling of the test products will match. Colorant will be added 
to the placebo to match the appearance of SHP640 and the PVP-I ophthalmic solution. Treatment 
assignment will be determined by the randomization schedule.
6.1.2
Commercially Obtained Investigational Product
Not Applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive response technology (IRT) vendor will be used for this study to manage packaged 
investigational medicinal product (IMP) supply, IMP shipments, receipt of IMP at clinical sites, 
randomization of IMP to subjects, expiry tracking, IMP returns, accountability of IMP, and 
emergency unmasking. 
6.2.2
Allocation of Subjects to Treatment 
This is a double-masked, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment is 
automatically assigned by the IRT.
Randomization will be stratified by age to maintain the randomization ratio among subjects 1 
month to <6 years, 6 to <18 years, and subjects ≥18 years. Subjects will be randomly assigned to 
receive SHP640, PVP-I 0.6%, or placebo based on a 3:1:3 ratio (SHP640:PVP-I:placebo) within 
the randomization strata.


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Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced randomization (Pocock and Simon 1975) will 
be used in this study to maintain the randomization ratio within each stratum. The randomization 
will be done centrally. 
6.2.3
Dosing
Subjects will be instructed to instill 1 drop of investigational product in each eye QID (with a 
minimum of 2 hours between doses) for 7 days.
Prior to administration of the first dose, the bottle should be removed from refrigeration and 
allowed to come to room temperature. The bottle will not be refrigerated before subsequent 
administrations. Storage requirements are discussed in Section 6.3.3.
The investigational product bottle should be shaken well prior to use at each dosing.
In-office dosing will only be performed at the first visit, and additionally if necessary. 
6.2.4
Unmasking the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor as soon as possible after the 
unmasking occurs. 
In the event that the treatment assignment is broken, the date and person who broke the code will 
be recorded by the IRT, and the reason for breaking will be recorded on the CRF. Upon breaking 
the mask, the subject will be withdrawn from the study but should complete Visit 5 (the end of 
study visit) to be followed up for safety purposes. Any code breaks that occur must be reported 
to the sponsor’s medical monitor. 
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and carton identification are applied to the investigational 
product(s) container. 
All investigational product is labeled with a minimum of the following: protocol number, 
medication identification number, dosage form, directions for use, storage conditions, expiry 
date (if applicable), batch number and/or packaging reference number, the statements “For 
clinical trial use only” and/or “CAUTION: New Drug – Limited by Federal (or US) Law to 
Investigational Use,” and the sponsor’s name and address. Any additional labeling requirements 
for participating countries and/or controlled substances will also be included on the label, if 
necessary.


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Space is allocated on the label so that the site representative can record the date dispensed, the 
subject’s initials (as permitted based on local laws), and the unique subject number.
Additional labels may, on a case-by-case basis, be applied to the investigational product in order 
to satisfy local or institutional requirements but must not: 

Contradict the clinical study label. 

Obscure the clinical study label. 

Identify the study subject by name. 
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers.
The investigational product bottle will be labeled and then placed into a 1x-labeled carton. This 
carton will then be secured with a tamper seal.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigational product must be stored at the site in a secure, refrigerated area (2-8ºC) 
accessible only to the investigator and his/her designees. The investigational product will be 
administered only to subjects enrolled in the clinical study, in accordance with the conditions 
specified in this protocol.
Undispensed investigational product should be stored under refrigeration at 2-8ºC.
Dispensed investigational product should be stored at room temperature below 30ºC. 
Investigational product should be protected from freezing and exposure to strong light.
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier and initials as permitted based on local laws 
on the investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system or a mechanical recording device such as a calibrated chart recorder or by 


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manual means, such that both minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required. Such a device (ie, certified min/max 
thermometer) would require manual resetting upon each recording. The sponsor must be notified 
immediately upon discovery of any excursion from the established range. Temperature 
excursions will require site investigation as to cause and remediation. The sponsor will determine 
the ultimate impact of excursions on the investigational product and will provide supportive 
documentation as necessary. Under no circumstances should the product be dispensed to subjects 
until the impact has been determined and the product is deemed appropriate for use by the 
sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
Not Applicable.
6.4
Drug Accountability  
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content, and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All dispensed medication 
will be documented on the CRFs and/or other investigational product record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the mask of the study is not compromised.
With the written agreement of the sponsor, at the end of the study all unused stock and 
empty/used investigational product packaging may be destroyed at the site or a local facility. In 
this case, destruction records identifying what was destroyed as well as when and how must be 


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obtained with copies provided to the sponsor. Destruction of investigational products must be in
accordance with local, state, and national laws.
If a site is not approved by the sponsor to destroy the investigational product, all used and unused 
stock is to be sent to a nominated contractor on behalf of the sponsor. Investigational products 
being returned to the sponsor’s designated contractors must be counted and verified by clinical 
site personnel and the sponsor (or designated contractor research organization [CRO]). Validated 
electronic return systems (ie, IRT) may not require a shipment form. Returned investigational 
products must be packed in a tamper-evident manner to ensure product integrity. Contact the 
sponsor for authorization to return any investigational product prior to shipment. Shipment of all 
returned investigational product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Subjects must be instructed to bring their investigational product and empty/used investigational 
product packaging to every visit. The pharmacist/nominated person will record details on the 
drug accountability form.
Subject compliance will be verified verbally during study visits. In cases of non-compliance, the 
investigator should determine if the medical monitor must be contacted for consultation. 


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7
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Assessments (see Table 1) and must be referred to in conjunction with the 
instructions provided in this section. Procedures or assessments that are not completed or are 
performed out of order should be captured as protocol deviations.
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject (as per 
local requirements). If a subject is younger than the legal age of consent (per local laws), the 
subject’s parent(s), guardian, or legally authorized representative will provide written informed 
consent; the subject will provide verbal or written assent as appropriate. There must be 
documentation of consent/assent (as per local requirements) indicating that the subject is aware 
of the investigational nature of the study and the required procedures and restrictions, prior to 
performing any study-related procedures. 
Where applicable, all procedures will be performed in both eyes.
7.1.1
Visit 1 (Day 1)
Screening and baseline/randomization will occur at Visit 1. Visit 1 assessments, beginning with 
informed consent, will be performed as outlined in Table 1.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product. Subjects cannot be rescreened once they have been designated as a 
screen failure.
A urine pregnancy test will be completed for all females of childbearing potential. The results 
will be read by site personnel and recorded in the source documents.
All AEs occurring after signature of informed consent must be recorded in the source documents 
and CRF. 
Prior to randomization, the procedures should be performed in the following order (in both eyes, 
as appropriate):

Informed consent (and assent, if applicable)

Inclusion/exclusion criteria

Medical history

Demographics

Concomitant medications

Urine pregnancy test (for women of childbearing potential)


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
Ocular discomfort scale

BCVA

Slit lamp biomicroscopy

Bulbar conjunctival injection evaluation

Ocular conjunctival discharge evaluation

Rapid Pathogen Screening, Inc. (RPS) AdenoPlus® test (if not previously conducted within 
24 hours of Visit 1)
If any findings during screening exams do not meet the inclusion/exclusion criteria, the subject is 
not eligible to be randomized. 
Eligible subjects must have a positive response in at least one eye. A positive response is defined 
as meeting ALL of the following criteria in the same eye:

Report presence of signs and/or symptoms of bacterial conjunctivitis for ≤3 days prior to 
Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival Injection 
Scale

Ocular conjunctival discharge: a grade of ≥1 (mild) on a 0-3 scale of Ocular Conjunctival 
Discharge Scale
Study eye will not be determined at Visit 1. All ophthalmic assessments will be conducted on 
both eyes. Selection of study eye for analyses will be according to the criteria outlined in 
Section 9.8.1.
The procedures should be performed in the following order:

Conjunctival bacterial culture collection (1 swab per eye) 

Non-dilated/dilated fundus examination

Randomization

Dispense and instill investigational product in both eyes by the designated site staff 
investigational product administrator. The investigational product bottle should be shaken 
well prior to use at each dosing.
All assessments, randomization, and medication instillation on Day 1 must take place with 
sufficient time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses).


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7.1.2
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8)
Visits 2 (Day 3), 3 (Day 5), and 4 (Day 8) assessments will be performed as outlined in Table 1
and as described in the Study Operations Manual. Assessments should be performed in 
descending order as listed.
Subject compliance will be verified verbally during study visits. In cases of non-compliance, the 
investigator should determine if the medical monitor must be contacted for consultation. 
Subjects should not instill investigational product within 12 hours of scheduled study visits. To 
ensure this, subjects should be reminded to not dose the morning of Visits 2, 3, and 4. 
Medication instillation should only be performed in-office if it is necessary and should be done 
once all other assessments are completed. Subjects who instill medication less than 12 hours 
before study visits will be recorded as protocol deviations.
7.1.3
Visit 5 (End of Study or Early Termination)
Safety follow-up will be conducted at Visit 5 (the end-of-study visit). Visit 5 (Day 12) 
assessments will be performed as outlined in Table 1. Assessments should be performed in 
descending order as listed.
Subjects who discontinue the study and proceed to Visit 5 for early termination should have 
investigational product collected, a compliance assessment, and drug accountability assessed at 
their final visit.
All AEs and serious AEs (SAEs) that are not resolved at the time of Visit 5 or early termination 
will be followed to closure (see Section 8.1).
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
7.2.1.1
Demographics
Demographic information will be collected at Visit 1. Date of birth (where permitted), age, sex, 
race, and ethnicity will be recorded.
7.2.1.2
Medication and Medical History
MEDICATION HISTORY
Refer to Section 5 for full details on collection of prior treatment.
The investigator will categorize treatments as ocular (specified as left eye, right eye, or both 
eyes) or non-ocular-based on the indication for use. Prior treatment information must be recorded 
on the appropriate CRF page. 


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MEDICAL HISTORY
The site must record all clinically or medically relevant information regardless of how much time 
has elapsed since the date of any diagnosis. Medical history will be classified as ocular or 
non-ocular by the investigator. History should include but is not limited to: 

History of ocular diseases/conditions 

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, and any other non-ocular diseases/underlying conditions within 
the past year prior to the screening visit (Visit 1)
7.2.1.3
RPS AdenoPlus Test
The RPS AdenoPlus test will be performed at Visit 1 (unless results are available from a test 
performed within 24 hours of Visit 1) as outlined in Table 1. A negative result in both eyes is 
required for enrollment in this study.
The RPS AdenoPlus test is an in-office test that allows for the detection of adenoviral antigens 
directly from human eye fluid. A small tear sample is transferred onto the AdenoPlus test, which 
confirms the presence of adenovirus and the viral form of conjunctivitis. 
Please refer to the Study Operations Manual for a detailed description of the RPS AdenoPlus 
Test and administration.
7.2.2
Efficacy
7.2.2.1
Clinical Resolution
Clinical resolution of bacterial conjunctivitis is defined as the absence (score=0) of bulbar 
conjunctival injection and watery conjunctival discharge in the study eye. Bulbar conjunctival 
injection will be assessed based on a 0-4 scale that uses pictures from the Validated Bulbar 
Redness (VBR) Scale, and watery conjunctival discharge will be assessed based on a 0-3 scale. 
Details of the bulbar conjunctival injection and watery conjunctival discharge scales are located 
in the Study Operations Manual.
7.2.2.2
Bacterial Eradication
Bacterial eradication is defined as absence of all bacterial species present at or above 
pathological threshold at baseline in the study eye. 
Pathological threshold for individual bacterial species will be based on colony-forming unit 
(CFU)/mL threshold levels established by Cagle and modified by Leibowitz for different ocular 
bacterial species found in the specimens collected from each subject (Leibowitz 1991). Bacterial 
species will be determined by Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass 
Spectrometry, using their protein patterns.
Additional details are located in the Study Operations Manual. 


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7.2.3
Safety
Safety assessments will be performed in both eyes.
7.2.3.1
Best Corrected Visual Acuity
The BCVA will be performed prior to slit lamp examination during the study as outlined in
Table 1. 
The complete instructions for performing the BCVA are in the Study Operations Manual. 
Changes in visual acuity (VA) will be assessed for clinical significance. Clinically significant 
changes should be recorded in the source and on the electronic CRF (eCRF) as an AE.
For subjects who are too young to use an ETDRS chart, an age-appropriate measurement method 
in accordance with the American Academy of Pediatrics’ (AAP) Policy Statement for Visual 
System Assessment in Infants, Children, and Young Adults by Pediatricians (Donahue and Baker 
2016; American Academy of Pediatrics 2016; located in the Study Operations Manual) should be 
used. The policy statement recommends that formal vision screening can begin at 3 years of age. 
VA measurements for children under the age of 3 will be done at the discretion of the 
investigator. If these are not done, the child should be able to fixate on and follow a moving 
object. VA is to be measured using the same method at all visits in the same subject.
7.2.3.2
Slit Lamp Biomicroscopy
Slit lamp biomicroscopy (or handheld slit lamp) will be performed during the study as outlined 
in Table 1. 
Observations will be graded as normal or abnormal. Abnormal findings will be described, and 
clinically significant abnormalities should be recorded in the source and on the eCRF (in medical 
history at screening; any changes from the screening visit may be recorded as AEs by the 
investigator). Please note the investigator may use his/her discretion to determine whether not 
clinically significant (NCS) and disease progression should be considered AEs). The following 
will be examined at each visit: 

Lids 

Conjunctiva 

Cornea

Anterior chamber

Iris

Lens
External examination and biomicroscopy will be performed using a slit lamp. Magnification will 
be consistent with standard clinical practice. The subject will be seated.
For infants and young children, if the above exams cannot be performed with a slit lamp or a 
hand held slit lamp, an external examination is to be conducted in accordance with the AAP’s


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Policy Statement for Visual System Assessment in Infants, Children, and Young Adults by 
Pediatricians (Donahue and Baker 2016; American Academy of Pediatrics 2016; located in the 
Study Operations Manual). The examination of lens in these subjects should be conducted at 
Visits 1 and 5 (or ET visit) and graded based on the external examination and red reflex exam 
(Section 7.2.3.3). All other structures listed above will be examined and graded at all visits based 
on the external examination. Observations will be graded as normal or abnormal. Abnormal 
findings will be described.
7.2.3.3
Non-dilated/Dilated Fundus Examination
Fundus examination must be conducted after BCVA, slit lamp biomicroscopy, and conjunctival 
swab for bacterial culture has been collected. 
A non-dilated fundus examination will be performed in all subjects with the exception of infants 
and uncooperative small children during the study as outlined in Table 1.
Observations will be graded as normal or abnormal. Abnormal findings will be described.
The following will be examined:

Vitreous

Optic erve

Macula
Clinically significant changes should be recorded in the source and on the eCRF as an AE.
If a non-dilated fundus exam is attempted and is not feasible, a dilated fundus exam should be 
conducted. The test should be conducted the same way (either dilated or non-dilated) at both 
Visits 1 and 5 (or ET).
For infants and small children in whom a fundus examination cannot be done, a red reflex exam 
will be conducted in accordance with the AAP Policy Statement for Visual System Assessment 
in Infants, Children, and Young Adults by Pediatricians (Donahue and Baker 2016; 
American Academy of Pediatrics 2016; located in the Study Operations Manual). Observations 
will be graded as normal or abnormal. Abnormal findings will be described. The red reflex 
should be normal (present and symmetrical for both eyes) at the screening/baseline visit.
7.2.3.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.) Any AE that occurs after the first dose of 
investigational product instillation will be considered a treatment-emergent AE (TEAE).
Adverse events may also be determined by the investigator during study examinations as 
mentioned in previous sections.


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7.2.3.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
All bioanalytical assays for the study will be validated following Food and Drug Administration 
(FDA)/International Conference on Harmonisation (ICH) guidelines, based on the method’s 
intended use. The clinical lab will only receive sample identification numbers and collection 
dates, and the lab results will then be transferred to the central lab for data analysis. The lab will 
not receive any information on subject treatment assignment.
One swab sample from inferior conjunctival cul-de-sac of each eye will be collected at all study 
visits for all bacterial testing.
Bacterial eradication as well as antibiotic sensitivity will be determined based on bacterial 
cultures using standard microbiological laboratory procedures. 
7.2.3.6
Pregnancy Test 
A urine pregnancy test is performed on all females of childbearing potential at Visits 1 and 5, or 
if pregnancy is suspected. Urine pregnancy test kits will be provided by the sponsor and read on 
site by qualified site personnel.
7.2.3.7
Health-related Quality of Life Assessments
Ocular discomfort associated with conjunctivitis symptoms will be assessed through the ocular 
discomfort scale (ODS). The ODS is composed of 3 items: pain, itching, and foreign body 
sensation. All items will be evaluated using a 0-10 scale. A separate scale will be administered 
for children younger than 8 years of age. Please see the Study operations manual for a detailed 
description of this assessment.


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8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, and Recording of Adverse 
Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event, including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.


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Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.


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8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign assessment can represent an AE if the 
change is clinically relevant or if, during treatment with the investigational product, a shift of a 
parameter is observed from a normal value to an abnormal value, or a further worsening of an 
already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory or vital sign values 
which were not present at the pre-treatment value observed closest to the start of study treatment, 
further investigations should be performed until the values return to within the reference range or 
until a plausible explanation (eg, concomitant disease) is found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign parameter is clinically significant 
and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant or the female partner of a male study 
participant must be reported within 24 hours to the Shire Global Pharmacovigilance and Risk 
Management Department using the Shire Investigational and Marketed Products Pregnancy 
Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy Report 
Form (and any applicable follow-up reports) must also be sent to the CRO/Shire medical monitor 
using the details specified in the emergency contact information section of the protocol. The 
pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine -hCG 
test or ultrasound result will determine the pregnancy onset date.


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8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category:

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: This includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol.)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a pre-specified total daily dose of 4 drops per eye of the product. 

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reported as a medication 
error.
The administration and/or use of an expired investigational product should be reported as a 
medication error.
In cases of overdose, the investigator should determine if the medical monitor must be contacted 
for consultation.
All investigational product provided to pediatric subjects should be administered or supervised 
by the parent(s)/guardian/legally authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure, which the 
sponsor has provided under separate cover to all investigators.


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8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO/Shire medical monitor 
within 24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see 
Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the CRO/Shire medical monitor using the details specified in the emergency 
contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires in-subject hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in in subject 
hospitalization, or the development of drug dependency or drug abuse. 


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8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject provides 
written informed consent (and assent, if applicable) until the defined follow-up period stated in 
Section 7.1.3 and must be reported to the Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and/or the clinical CRO is responsible for notifying the relevant regulatory 
authorities and Institutional Review Boards (IRBs)/ethics committees (ECs) of related, 
unexpected SAEs.
In addition, the sponsor and/or the clinical CRO is responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the SHP640 
program. 


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The investigator is responsible for notifying the local IRB, local EC, or relevant local regulatory 
authority of all SAEs that occur at his or her site as required.


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9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigator’s authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the CRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRF Completion Guidelines. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unmask the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unmasking, any data that may unmask study team personnel 
will be presented as masked information or otherwise will not be made available. If applicable, 
unmasked data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be addressed.
In addition to a final SAP for the final analysis, a separate SAP for the interim analysis will be 
finalized prior to unmasking and performing the interim analysis. The SAP for the final analysis 


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will be finalized prior to unmasking of the study to preserve the integrity of the statistical 
analysis and study conclusions. 
All final statistical analyses will be performed after the database is locked and unmasked.
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513) Version 
9.2 or higher. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
An unmasked interim analysis (IA) will be performed after ~50% subjects exit the trial in the 
modified intent-to-treat (mITT) population (ie, n=252 in mITT), with data to be analyzed entered 
into the database, queried, and discrepancies resolved. The purpose of the IA will be to assess the 
adequacy of the initial sample size estimation by evaluating conditional power for the primary 
comparison of SHP640 versus placebo on clinical resolution in the treatment of subjects with 
bacterial conjunctivitis in the study eye at Visit 3 (Day 5). There is no intention to stop early for 
efficacy or futility based on the results from the IA. 
The IA will be performed by an external unmasked independent statistician and/or unmasked 
programmers based on a prespecified interim SAP. The interim SAP will explicitly describe how 
the conditional power is to be calculated and the precise rules for altering the sample size 
depending on the potential results. The interim SAP will be finalized prior to IA. The interim 
statistical report including the results will be distributed only to a limited group of people who 
are not involved in the conduct of the trial. All sponsor, CRO, and site staff involved in the 
conduct of the trial must remain masked throughout the trial. Recommendation from the IA to 
increase the sample size may require an amendment to the study protocol. No adjustment of type
I error rate is needed because the sole purpose of the planned IA is to adjust the sample size by 
using the conditional power approach, and the sample size will be changed only under certain 
conditions (Mehta and Pocock 2011).
9.6
Sample Size Calculation and Power Considerations
The sample size was estimated for the primary comparison of SHP640 versus placebo on clinical 
resolution in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 
(Day 5) using nQuery Advisor 7.0. Subjects will be randomized 3:1:3 to receive either SHP640, 
PVP-I, or placebo within each age stratum. 
A sample size of 504 subjects (216 subjects in each of the SHP640 and placebo groups, 72 in 
PVP-I group) will ensure ~90% power to compare the SHP640 and placebo treatment groups 
assuming 61% and 45% subjects with clinical resolution, respectively, using Fisher’s Exact test 
at 2-sided 5% level of significance. All efficacy analyses will be based on the mITT with post-
baseline last observation carried forward for the subjects with missing clinical resolution status 
as Visit 3 (Day 5).
An exploratory PVP-I arm (ie, 72 subjects in mITT and approximately 103 randomized subjects) 
will be included in the trial to provide parameter estimates on PVP-I treatment effect to inform 
future studies. No formal hypothesis testing will be conducted on the PVP-I arm. 


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To ensure 504 subjects in the mITT population, approximately 721 subjects will be randomized 
in this study (approximately 309 subjects in each of SHP640 and placebo groups; approximately 
103 subjects in PVP-I group).
9.7
Study Population
The safety population will include all subjects who receive at least 1 dose of investigational 
product.
The intent-to-treat (ITT) population will include all randomized subjects. 
The mITT population consists of a subset of the ITT population who receive at least 1 dose of 
investigational product and have a positive bacterial culture (presence of 1 or more bacterial 
species at or above pathological threshold) at baseline in the study eye.
9.8
Efficacy Analyses
The analyses on primary, key secondary, secondary, and exploratory efficacy endpoints will be 
performed on the mITT population and will be presented by treatment group. 
Additional sensitivity analyses may be conducted in the ITT population.
For both efficacy and safety analyses, baseline is defined as the assessments taken prior to 
treatment at Visit 1 (Day 1).
9.8.1
Study Eye Designation
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a 
score of at least 1 for both ocular conjunctival discharge and bulbar conjunctival redness at 
baseline (baseline is defined as the assessments taken prior to treatment at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive bacterial culture (presence of 1 
or more bacterial species at or above pathological threshold) at baseline or both eyes eligible 
and both with a non-positive bacterial culture (absence of any bacterial species at or above 
pathological threshold) at baseline, the study eye will be the eye with the highest global 
clinical score (sum of bulbar conjunctival injection and ocular conjunctival discharge) at 
baseline. If both eyes have the same global clinical score at baseline, then the study eye will 
be the right eye. 

For subjects with both eyes eligible with a positive bacterial culture in 1 eye at baseline, the 
baseline bacterial culture positive eye will be the study eye. 

For subjects with only 1 eligible eye, the eligible eye will be the study eye irrespective of its 
baseline bacterial culture result. 
The study eye designation is summarized in the table below:


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Eligible Eye(s)
Bacterial Culture Results
Study Eye
Both eyes
Both eyes positive
Highest global clinical score at Visit 1 (Day 1)
(or right eye if scores are the same)
Both eyes
Both eyes negative
Highest global clinical score at Visit 1 (Day 1)
(or right eye if scores are the same)
Both eyes
One eye positive
The bacterial culture positive eye at Visit 1 (Day 1) 
One eye
Positive or negative for either eye
The eligible eye 
9.8.2
Primary Efficacy Endpoint
The primary efficacy endpoint is clinical resolution status (defined as absence [ie, a score of 0] 
of bulbar conjunctival injection and ocular conjunctival discharge) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo.
All efficacy analyses will be performed on the mITT population and presented by treatment 
groups. There is a single primary comparison for the single primary endpoint. Therefore, no 
adjustment of multiplicity is needed for the hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 5) will be 
compared between the SHP640 and placebo group. The comparison will be based on the 
proportion of subjects with clinical resolution in the study eye at Visit 3 (Day 5) using Fisher’s 
Exact test at 2-sided 0.05 significance level. 
If subjects have missing clinical resolution status at Visit 3 (Day 5), then the last post-baseline 
observation will be carried forward for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with 
clinical resolution in the study eye between SHP640 ophthalmic solution and placebo with the 
alternative of the non-zero difference in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 2-sided Fisher’s Exact 
test at 5% level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical 
method(s) including other methods of imputation of missing data. Sensitivity analyses may be 
conducted in the ITT population in addition to the mITT. In addition, descriptive statistics will 
be generated for the primary efficacy endpoint by treatment within the overall pediatric 
population (ie, 1 month to 18 years) and within each pediatric age stratum (1 month to <6 years 
and 6 to <18 years) in mITT if pediatric subjects enrolled in the study are relatively well 
distributed across both pediatric subgroups in mITT. A detailed plan for primary analysis 
including additional sensitivity analyses will be described in the SAP.
9.8.3
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoint is bacterial eradication status (defined as absence of all 
bacterial species present at or above pathological threshold at baseline) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo.


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All efficacy analyses will be performed on the mITT population and presented by treatment 
groups. In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary 
hypotheses will be tested sequentially. Each hypothesis will be tested using Fisher’s Exact test at 
2-sided 5.0% level with null hypothesis of no difference in the proportion of subjects for the 
endpoint between the 2 treatment groups. 
First, the primary efficacy endpoint will be tested. Only if the null hypothesis for the primary 
efficacy endpoint is rejected at 5.0% level, then the key secondary efficacy endpoint of bacterial 
eradication will be tested to compare the proportion of subjects with bacterial eradication 
between the SHP640 and placebo treatment group. If subjects have missing bacterial eradication 
status at Visit 3 (Day 5), then the last post-baseline observation will be carried forward for the 
determination of bacterial eradication of the study eye. 
Sensitivity analyses will also be done on key secondary efficacy endpoints using similar methods 
as described above. In addition, descriptive statistics will be generated for the key secondary 
efficacy endpoint by treatment within the overall pediatric population (ie, 1 month to 18 years) 
and within each pediatric age stratum (1 month to <6 years and 6 to <18 years) in the mITT 
population if pediatric subjects enrolled in the study are relatively well distributed across both 
pediatric subgroups in mITT. Details on the analyses will be described in the SAP.
9.8.4
Secondary Efficacy Endpoints
All secondary efficacy analyses will be performed on the mITT population and presented by 
treatment group. No hypothesis testing is planned for the secondary efficacy endpoints. All 
secondary efficacy endpoint will be summarized by treatment groups using descriptive statistics 
at each assessment visit. Continuous endpoints will be summarized by number of subjects (n), 
mean, median, standard deviation, minimum, maximum, and confidence intervals (CIs). Binary 
endpoints will be summarized by number of subjects (n), frequencies, proportions, and CIs.
Secondary efficacy endpoints are defined as follows:

Clinical resolution status of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12) in the study eye

Bacterial eradication status (defined as absence of all bacterial species present at or above 
pathological threshold at baseline in the study eye) as assessed by bacterial culture at Visits 2 
(Day 3), 4 (Day 8), and 5 (Day 12) in the study eye

Absolute and change from baseline of the individual clinical signs score (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12) in the study eye

The global clinical score (defined as the sum of bulbar conjunctival injection and ocular 
conjunctival discharge) and change from baseline in the global clinical score at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye


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
Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with 
neither injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8),
and 5 (Day 12) in the study eye

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8),
and 5 (Day 12) in the study eye
9.8.5
Exploratory Efficacy Endpoints
The ocular discomfort endpoints will be evaluated by absolute and change from baseline of 
ocular discomfort scores (or by the binary ocular discomfort endpoint for children younger than 
8 years of age) due to conjunctivitis symptoms at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12). 
No hypothesis testing is planned for the exploratory efficacy endpoint. Exploratory endpoints 
will be summarized using methods similar to secondary endpoints.
9.9
Safety Analyses
Safety data will be presented for the safety population by treatment group and overall.
Safety data collected at baseline prior to treatment (Visit 1/Day 1) will be used as the baseline 
value for safety analysis.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The 
number of subjects and percentage with a TEAE as well as the number of TEAEs will be 
calculated overall, by system organ class, by preferred term, and by treatment group. 
Treatment-emergent adverse events will be further summarized by severity and relationship to 
investigational product. Adverse events related to investigational product, AEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized and listed.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or a 
non-ocular AE.
The following safety endpoints will be descriptively summarized by treatment group at each 
applicable visit:

BCVA

Slit lamp biomicroscopy

Lid 

Conjunctiva 

Cornea 

Anterior chamber 

Iris

Lens 


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
Non-dilated/dilated fundus examination

Vitreous 

Optic nerve 

Macula 

Urine pregnancy testing (for females of childbearing potential)
9.10
Other Analyses
No other analyses are planned in this study.


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10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, European Union 
(EU) Directive 2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC and its updates, as well as all applicable national and local laws and 
regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of


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the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study that has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC and its updates, and applicable regulatory requirements and 
guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
The coordinating principal investigator will be assigned and selected based on the extent of their 
involvement in the study and experience in the therapeutic area.
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met


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protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs to ensure accurate and timely information is provided at all 
phases during the study may be done by the sponsor, applicable CRO, investigator, or, for 
multicenter studies, coordinating principal investigator according to national provisions and will 
be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data. All corrections to the eCRF must indicate the reason for 
change. If corrections are made after the review and signature by the investigator, he or she must 
be made aware of the change, and his or her awareness must be documented by re-signing the 
eCRF.   
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include but are not limited to the 
subject’s medical file, scales, ODS, and documented results of AdenoPlus test results.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.


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The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) will check the CRF 
entries against the source documents. The consent form includes a statement by which the
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
European Medicines Agency (EMA), United Kingdom Medicines and Healthcare products 
Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation, or honoraria; any proprietary interest in investigational product; and any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to 
the objectives, potential benefits and risk, inconveniences, and subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 


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into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent(s)/guardian/legally authorized representative/caregiver of the safe, responsible 
storage and administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form and assent form, 
where applicable, that was reviewed by the IRB/EC and received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 


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1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the CRO.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP640; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, other information (eg, initials and 
date of birth if the local law permits) may also be collected and used to assist the sponsor to 
verify the accuracy of the data (eg, to confirm that laboratory results have been assigned to the 
correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to 
and used in other countries that may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 


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letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.


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11
REFERENCES
American Academy of Pediatrics 2016. Visual system assessment in infants, children, and young 
adults by pediatricians. Pediatrics, 137, 28-30.
Azari, A. A. & Barney, N. P. 2013. Conjunctivitis: a systematic review of diagnosis and 
treatment. Jama, 310, 1721-9.
Capriotti, J. A., Stewart, K. P. & Pelletier, J. 2010. The unique challenges of viral conjunctivitis -
Its similarities to bacterial infection belie key differences that impact clinical care 
[Online]. Ophthalmology Management. Available: 
http://www.ophthalmologymanagement.com/articleviewer.aspx?articleid=104651.
Cdc. 2010. Conjunctivitis (pink eye) [Online]. Centers for Disease Control and Prevention. 
Available: http://www.cdc.gov/conjunctivitis/clinical.html.
Chen, C. J. & Starr, C. E. 2008. Epidemiology of gram-negative conjunctivitis in neonatal 
intensive care unit patients. Am J Ophthalmol, 145, 966-970.e2.
Dias, C., Gonçalves, M. & João, A. 2013. Epidemiological study of hospital-acquired bacterial 
conjunctivitis in a level III neonatal unit. Sci World J, 1-5.
Donahue, S. P. & Baker, C. N. 2016. Procedures for the Evaluation of the Visual System by 
Pediatricians. Pediatrics, 137.
Ford, E., Nelson, K. E. & Warren, D. 1987. Epidemiology of epidemic keratoconjunctivitis. 
Epidemiol Rev, 9, 244-61.
Gordon, Y. J., Gordon, R. Y., Romanowski, E. & Araullo-Cruz, T. P. 1993. Prolonged recovery 
of desiccated adenoviral serotypes 5, 8, and 19 from plastic and metal surfaces in vitro. 
Ophthalmology, 100, 1835-9; discussion 1839-40.
Haas, J., Larson, E., Ross, B., See, B. & Saiman, L. 2005. Epidemiology and diagnosis of 
hospital-acquired conjunctivitis among neonatal intensive care unit patients. Pediatr 
Infect Dis J, 24, 586-589.
Leibowitz HM, 1991. Antibacterial Effectiveness of Ciprofloxacin 0.3°/o Ophthalmic Solution in 
the Treatment of Bacterial Conjunctivitis. American Journal of Ophthalmology l12:295-
335.
Mehta, C. R. & Pocock, S. J. 2011. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Statistics in medicine, 30, 3267-84.
Mundipharma Ag 2004. Betadine Prescribing Information.
Nauheim, R. C., Romanowski, E. G., Araullo-Cruz, T., Kowalski, R. P., Turgeon, P. W., Stopak, 
S. S. & Gordon, Y. J. 1990. Prolonged recoverability of desiccated adenovirus type 19 
from various surfaces. Ophthalmology, 97, 1450-3.
Novartis 2007. Maxidex Prescribing Information.
O'brien, T. P., Jeng, B. H., Mcdonald, M. & Raizman, M. B. 2009. Acute conjunctivitis: truth 
and misconceptions. Curr Med Res Opin, 25, 1953-61.
Patel, P. B., Diaz, M. C. G., Bennett, J. E. & Attia, M. W. 2007. Clinical features of bacterial 
conjunctivitis in children. Clin Investigations, 1-5.
Pelletier, J. S., Stewart, K., Trattler, W., Ritterband, D. C., Braverman, S., Samson, C. M., Liang, 
B. & Capriotti, J. A. 2009. A combination povidone-iodine 0.4%/dexamethasone 0.1% 
ophthalmic suspension in the treatment of adenoviral conjunctivitis. Adv Ther, 26, 776-
83.
Pelletier, M. R., Casella, L. G., Jones, J. W., Adams, M. D., Zurawski, D. V., Hazlett, K. R., Doi, 
Y. & Ernst, R. K. 2013. Unique structural modifications are present in the 


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lipopolysaccharide from colistin-resistant strains of Acinetobacter baumannii. Antimicrob 
Agents Chemother, 57, 4831-40.
Pocock, S. J. & Simon, R. 1975. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 31, 103-15.
Rours, I. G. I. J. G., Hammerschlag, M. R., Ott, A., De Faber, T. J. T. H. N., Verbrugh, H. A., De 
Groot, R. & Verkooyen, R. P. 2008. Chlamydia trachomatis as a cause of neonatal 
conjunctivitis in Dutch infants. Pediatrics, 121, e321.
Statham, M. O., Sharma, A. & Pane, A. R. 2008. Misdiagnosis of acute eye diseases by primary 
health care providers: incidence and implications. Med J Aust, 189, 402-4.
Visscher, K. L., Hutnik, C. M. & Thomas, M. 2009. Evidence-based treatment of acute infective 
conjunctivitis: Breaking the cycle of antibiotic prescribing. Can Fam Physician, 55, 
1071-5.


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12
APPENDICES




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APPENDIX 2 SCALES AND ASSESSMENTS
All scales assessments referenced in the protocol, including procedural instructions for the 
investigator, are in the Study Operations Manual and the Laboratory Manual (provided upon 
request).

SAP_005.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
SHP640-303 
Protocol Title: 
A Phase 3, Multi-center, Randomized, Double-Masked 
Study to Evaluate the Clinical Efficacy and Safety of 
SHP640 (PVP-Iodine 0.6% and Dexamethasone 0.1%) 
Ophthalmic Suspension Compared to Placebo in the 
Treatment of Bacterial Conjunctivitis 
Drug: 
SHP640 
Sponsor:  
Shire 
300 Shire Way, Lexington, MA 02421 USA 
Version No. and Date 
Protocol Amendment 3: Dec 13, 2017 
 
Version No: 
Document History 
Description of Update 
Author(s) 
Effective Date 
Version 1.0 
Final Version 
June 22, 2018 
Amendment 
1.0 
In Section 6, PD categories were 
updated 
according 
to 
CTMS 
classifications. 
In Section 8.2, derivation rule for total 
number of expected doses was updated. 
In Section 10, how to handle subjects 
with 
no 
post 
baseline 
efficacy 
assessment in the analyses 
were 
clarified. 
In Section 11.2, change from baseline 
BCVA has been added. 
In Section 18.4, LOCF and WOCF 
derivation was clarified. 
Nov 8, 2018 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................4 
LIST OF FIGURES .........................................................................................................................4 
ABBREVIATIONS .........................................................................................................................5 
1. 
INTRODUCTION ....................................................................................................................6 
2. 
STUDY DESIGN .....................................................................................................................7 
2.1 
General Study Design .................................................................................................7 
2.2 
Randomization ...........................................................................................................7 
2.3 
Masking ......................................................................................................................8 
2.4 
Schedule of Assessments ...........................................................................................8 
2.5 
Determination of Sample Size ..................................................................................10 
2.6 
Multiplicity Adjustments for Type I Error Control ..................................................10 
3. 
OBJECTIVES .........................................................................................................................12 
3.1 
Primary Objective ....................................................................................................12 
3.2 
Secondary Objective ................................................................................................12 
3.3 
Exploratory Objective ..............................................................................................13 
4. 
SUBJECT POPULATION SETS ...........................................................................................14 
4.1 
Screened Population .................................................................................................14 
4.2 
Safety Population .....................................................................................................14 
4.3 
Intent to Treat (ITT) Population ...............................................................................14 
4.4 
Modified Intent to Treat (mITT) population ............................................................14 
5. 
SUBJECT DISPOSITION ......................................................................................................15 
6. 
PROTOCOL DEVIATIONS ..................................................................................................16 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................17 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE .......................................18 
8.1 
Exposure to Investigational product .........................................................................18 
8.2 
Measurement of Treatment Compliance ..................................................................18 
9. 
PRIOR AND CONCOMITANT MEDICATION ..................................................................19 
10. EFFICACY ANALYSES .......................................................................................................20 
10.1 
Study Eye Designation .............................................................................................20 
10.2 
Primary Efficacy Endpoint and Analysis .................................................................21 
10.3 
Sensitivity Analyses for the Primary Efficacy Endpoint .........................................21 
10.4 
Exploratory Analyses for the Primary Efficacy Endpoint .......................................23 
10.5 
Key Secondary Efficacy Endpoints and Analysis ....................................................23 
10.6 
Other Secondary Efficacy Endpoints and Analysis .................................................24 
10.7 
Exploratory Efficacy Endpoints and Analyses .........................................................25 


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11. SAFETY ANALYSES ...........................................................................................................26 
11.1 
Adverse Events .........................................................................................................26 
11.2 
Other Safety Variables .............................................................................................27 
12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ............28 
13. OTHER ANALYSES .............................................................................................................29 
14. INTERIM ANALYSIS ...........................................................................................................30 
15. DATA MONITORING/REVIEW COMMITTEE .................................................................31 
16. COMPUTER METHODS ......................................................................................................32 
17. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .................................................33 
18. DATA HANDLING CONVENTIONS ..................................................................................34 
18.1 
General Data Reporting Conventions ......................................................................34 
18.2 
Study Visits and Windows .......................................................................................34 
18.3 
Derived Efficacy Endpoints .....................................................................................35 
18.4 
Repeated or Unscheduled Assessments of Safety Parameters .................................35 
18.5 
Missing Date of Investigational Product ..................................................................36 
18.6 
Missing Date Information for Prior or Concomitant Medications ...........................36 
18.6.1 
Incomplete Start Date ........................................................................................36 
18.6.2 
Incomplete Stop Date ........................................................................................37 
18.7 
Missing Date Information for Adverse Events ........................................................37 
18.7.1 
Incomplete Start Date ........................................................................................37 
18.8 
Missing Severity Assessment for Adverse Events ...................................................38 
18.9 
Missing Relationship to Investigation Product for Adverse Events ........................38 
19. REFERENCES .......................................................................................................................39 
20. APPENDIX.............................................................................................................................40 
20.1 
Threshold Criteria for Judging Culture Positive Specimens ....................................40 
20.2 
Example SAS Code ..................................................................................................41 
20.2.1 
Example SAS Code for Fisher’s Exact Test and the CIs ..................................41 
20.2.2 
Example SAS Code for Multiple Imputation ....................................................42 
20.2.3 
Example SAS Code for Adjusted Chi-square Test ...........................................44 
20.2.4 
Example SAS Code for Generating Descriptive Statistics ...............................47 
21. TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS ..............................48 


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LIST OF TABLES 
Table 1 
Schedule of Assessments ......................................................................................... 9 
Table 2:  
Visit Windows (Study Day Based) ........................................................................ 34 
 LIST OF FIGURES  
Figure 1: 
SHP640-303 Study Design ...................................................................................... 7 


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ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
CC-IFA 
cell culture-immunofluorescence assay 
CFU 
colony forming unit 
CI 
confidence interval 
CRF 
case report form 
CTMS 
Clinical Trial Management System 
eCRF 
electronic case report form 
GCS 
Global clinical score 
HSV 
Herpes Simplex Virus 
IRT 
interactive response technology 
ITT 
Intent To Treat 
LOCF 
last observation carried forward 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent To Treat 
PVP-I 
povidone-iodine 
qPCR 
quantitative polymerase chain reaction 
RPS 
Rapid Pathogen Screening, Inc. 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SE 
standard error 
TEAE 
treatment-emergent adverse event 
VBR 
Validated Bulbar Redness 
WHO-DD 
World Health Organization – Drug Dictionary 
WOCF 
worst observation carried forward 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of efficacy and safety data as described in the final study protocol amendment 3.0 dated 
Dec 13, 2017. Specifications for tables, figures, and listings are contained in a separate 
document.   


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2. 
STUDY DESIGN  
2.1 
General Study Design 
SHP640-303 is a global, multicenter, randomized, double-masked, parallel-group, placebo-
controlled study designed to demonstrate the safety and efficacy of SHP640 ophthalmic 
suspension compared to placebo in treating bacterial conjunctivitis. In addition, an exploratory 
arm of povidone-iodine (PVP-I) 0.6% ophthalmic solution will be included. 
Once screening and baseline assessments are complete and subjects are confirmed eligible to 
enroll in the study, subjects will be randomized, and investigational product (IP) will be 
administered on the same day (Day 1). The first dose will be administered by site staff on Day 1, 
and thereafter subjects will administer 1 drop in each eye 4 times a day (QID) for 7 days. 
Additional visits will occur on Days 3 (Visit 2), 5 (Visit 3), 8 (Visit 4), and 12 (Visit 5). All 
follow-up procedures will be conducted at Visit 5 (Day 12). The study will last up to 13 days.  
Figure 1 provides the study design. 
Figure 1: SHP640-303 Study Design 
 
 
2.2 
Randomization 
This is a double-masked, placebo-controlled study. The actual treatment given to individual 
subject is determined by a randomization schedule. 
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment is 
automatically assigned by the interactive response technology (IRT). 
Approximately 721 subjects will be randomized into the study at Visit 1 (Day 1). Randomization 
will be stratified by age to maintain the randomization ratio among subjects <6 years, 6 to <18 


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years, and subjects ≥18 years. Subjects will be randomized 3:1:3 to receive either SHP640, PVP-
I, or placebo within each stratum.  
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced allocation (Pocock and Simon, 1975) will be 
used in this study to maintain the randomization ratio within each stratum.  
2.3 
Masking  
This is a double-masked study.  The packaging, appearance, and labeling of the test products will 
match. Colorant will be added to the placebo to match the appearance of SHP640 ophthalmic 
suspension and the PVP-I ophthalmic solution. 
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor as soon as possible after the 
unmasking occurs. 
In the event that the treatment assignment is broken, the date and person who broke the code will 
be recorded by the interactive response technology (IRT), and the reason for breaking will be 
recorded on the electronic case report form (eCRF). Upon breaking the mask, the subject will be 
withdrawn from the study but should complete Visit 5 (the end of study visit) to be followed up 
for safety purposes. Any code breaks that occur must be reported to the sponsor’s medical 
monitor. 
The final unmasking of the data will occur after all the data has been received, appropriately 
reviewed and checked, and the database has been locked per Shire's SOPs.  Final analyses will 
be performed after the official database release using the unmasked data. 
2.4 
Schedule of Assessments  
Table 1 below presents the schedule of assessments. 


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Table 1 
Schedule of Assessments 
Procedure 
(All 
ocular 
assessments 
and 
procedures performed bilaterally) 
Visit 1 
Screeninga and 
Baseline 
(Day 1) 
-1 Day 
Visit 2 
(Day 3) 
+1 Day 
Visit 3 
(Day 5) 
Visit 4 
(Day 8) 
+1 Day 
Visit 5b 
(Day 12) 
+2 Days 
Informed consent/assenta 
X 
 
 
 
 
Inclusion/exclusion criteriaa 
X 
 
 
 
 
Medical history  
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
Urine pregnancy test 
Xc 
 
 
 
Xc 
Ocular discomfort scale 
X 
X 
X 
X 
X 
Best corrected visual acuity 
X 
X 
X 
X 
X 
Slit lamp biomicroscopy 
X 
X 
X 
X 
X 
Bulbar 
conjunctival 
injection 
evaluation 
X 
X 
X 
X 
X 
Ocular 
conjunctival 
discharge 
evaluation 
X 
X 
X 
X 
X 
AdenoPlus® test 
Xd 
 
 
 
 
Conjunctival 
swab 
for 
bacterial 
culturee 
X 
Xf 
Xf 
Xf 
X 
Conjunctival swab to test for HSV, 
and chlamydia and gonorrheal 
X 
 
 
 
 
Non-dilated/dilated 
fundus 
examinationk 
X 
 
 
 
X 
Randomizationg 
X 
 
 
 
 
Dispense investigational producth 
X 
 
 
 
 
Instill investigational product 
Xh 
Xi 
Xi 
 
 
Collect investigational product 
 
 
 
X 
Xb 
Compliance assessment 
 
X 
X 
X 
Xb 
Drug accountability 
 
 
 
X 
Xb 
Adverse events 
Xj 
X 
X 
X 
X 
Study completion 
 
 
 
 
X 
ET=early termination;  
a Informed consent and confirmation of inclusion/exclusion criteria can be conducted on Day -1; these criteria must be 
reconfirmed on Day 1. 
b If investigational product is discontinued, regardless of the reason, all discontinued subjects should proceed to Visit 5 whenever 
possible. Subjects who discontinue the study and proceed to Visit 5 should perform all Visit 5 assessments as well as drug return, 
compliance, and accountability. 
c Women of childbearing potential, prior to enrollment and at exit from the study 
d If not previously conducted within 24 hours of Visit 1 (Day 1)  
e One swab sample from inferior conjunctival cul-de-sac of each eye will be collected for all bacterial testing. 
f Conjunctival swab samples MUST be taken at least 12 hours after the last dose of investigational product at Visits 2, 3, 4, and 
ET, if applicable. 
g All assessments, randomization, and investigational product instillation on Day 1 must take place with sufficient time to allow 


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Table 1 
Schedule of Assessments 
Procedure 
(All 
ocular 
assessments 
and 
procedures performed bilaterally) 
Visit 1 
Screeninga and 
Baseline 
(Day 1) 
-1 Day 
Visit 2 
(Day 3) 
+1 Day 
Visit 3 
(Day 5) 
Visit 4 
(Day 8) 
+1 Day 
Visit 5b 
(Day 12) 
+2 Days 
all 4 Day 1 doses (with a minimum of 2 hours between doses). 
h The investigational product bottle should be shaken well prior to use at each dosing. The first dose will be administered by site 
staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a day for 7 days. 
i Investigational product instillation should only be performed in-office if it is necessary. 
j Monitoring for adverse events will begin after informed consent is obtained. 
k If a non-dilated fundus exam is not feasible, a dilated examination should be conducted. For each subject, the exam should be 
conducted the same way (either non-dilated or dilated) at both Visits 1 and 5 (or ET).   
l This sample will be used for baseline HSV testing for all subjects. For subjects <2 months of age, testing for chlamydia and 
gonorrhea detection will also be conducted using the same sample. 
 
2.5 
Determination of Sample Size 
The sample size was estimated for the primary comparison of SHP640 versus placebo on clinical 
resolution in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 
(Day 5) using nQuery Advisor 7.0. Subjects will be randomized 3:1:3 to receive either SHP640, 
PVP-I, or placebo within each age stratum.  
The primary efficacy endpoint is clinical resolution status (defined as absence [ie, a score of 0] 
of bulbar conjunctival injection and ocular conjunctival discharge) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo. The null hypothesis to be tested is that there is no 
difference in proportion of subjects with clinical resolution in the study eye between SHP640 
ophthalmic suspension and placebo with the alternative of the non-zero difference in the 
proportion with clinical resolution between them. 
A sample size of 504 subjects (216 subjects in each of the SHP640 and placebo groups, 72 in 
PVP-I group) will ensure ~90% power to compare the SHP640 and placebo treatment groups 
assuming 61% and 45% subjects with clinical resolution, respectively, using Fisher’s Exact test 
at 2-sided 5% level of significance.  
All efficacy analyses will be based on the modified Intent-to-Treat (mITT) population (refer to 
Section 4.4 for the definition of mITT) with post-baseline last observation carried forward 
(LOCF) for the subjects with missing clinical resolution status at Visit 3 (Day 5).  To ensure 504 
subjects in the mITT population, approximately 721 subjects will be randomized in this study 
(approximately 309 subjects in each of SHP640 and placebo groups; approximately 103 subjects 
in PVP-I group). 
2.6 
Multiplicity Adjustments for Type I Error Control 
An unmasked interim analysis (IA) will be performed after ~50% subjects exit the trial in the 
mITT population for possible sample size increase. The final sample size will be calculated in 
the unmasked IA based on the conditional power for the primary comparison of SHP640 versus 
placebo on clinical resolution in the treatment of subjects with bacterial conjunctivitis in the 


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study eye at Visit 3 (Day 5).  There is no inflation of type I error from this IA because the sole 
purpose of the IA is to adjust the sample size by using the conditional power approach, and the 
sample size will be changed only under certain conditions (Mehta and Pocock, 2011). However, 
for conservativeness, two sided 0.0001 alpha will be spent for the proposed IA and a two sided 
alpha of 0.0499 will be used for final analyses. 
Formal hypothesis testing will be conducted on the primary efficacy endpoint and key secondary 
efficacy endpoint with a total of 2 pairwise comparisons. The comparison on the primary 
efficacy endpoint will be based on clinical resolution in the study eye at Visit 3 (Day 5) between 
SHP640 and placebo in the mITT population. The comparison on the key secondary efficacy 
endpoint will be based on bacterial eradication in the study eye at Visit 3 (Day 5) between 
SHP640 and placebo in the mITT population. 
A fixed sequence procedure will be used to maintain the study-wide Type I error at 4.99% for 
final analyses with the primary efficacy endpoint being tested first and the key secondary 
efficacy endpoint being tested second. Both the primary and key secondary hypothesis tests will 
be conducted at the two-sided 0.0499 significance level following the pre-specified order.  The 
hypothesis test for the key secondary efficacy endpoint will not be performed unless the 
hypothesis test for the primary efficacy endpoint is statistically significant.  


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3. 
OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical 
resolution (defined as absence of bulbar conjunctival injection and ocular conjunctival discharge) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye 
at Visit 3 (Day 5).  
3.2 
Secondary Objective 
The key secondary objective is to evaluate the efficacy of SHP640 based on bacterial eradication 
(defined as absence of all bacterial species present at or above pathological threshold at baseline) 
compared with placebo in the treatment of subjects with bacterial conjunctivitis in the study eye 
at Visit 3 (Day 5). 
Other secondary objectives of this study are as follows: 
• To evaluate the effect of treatment in the study eye, for the following endpoints:  
• Clinical resolution of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12) 
• Bacterial eradication at Visits 2 (Day 3), 4 (Day 8), and 5 (Day 12)  
• Absolute and change from baseline of the individual clinical signs (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12) 
• The global clinical score (sum of bulbar conjunctival injection and ocular conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 5), 4 (Day 8), and 5 (Day 12)  
• Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12)  
• Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither 
injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 
5 (Day 12)  
• Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 
(Day 8), and 5 (Day 12)  
• To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the 
treatment of subjects with bacterial conjunctivitis 
• Use of rescue medication 


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3.3 
Exploratory Objective 
The exploratory objective of this study is as follows:  
• To evaluate ocular discomfort due to conjunctivitis symptoms in subjects receiving 
SHP640 compared to PVP-I and placebo at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12) 


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4. 
SUBJECT POPULATION SETS 
4.1 
Screened Population 
The Screened Population will consist of all subjects who have provided written informed 
consent. 
4.2 
Safety Population 
The Safety Population will consist of all subjects who receive at least one dose of investigational 
product. 
4.3 
Intent to Treat (ITT) Population 
The Intent-to-Treat (ITT) Population will include all randomized subjects. 
4.4 
Modified Intent to Treat (mITT) population 
The mITT Population consists of a subset of the ITT population who receive at least one dose of 
investigational product and have a positive bacterial culture (presence of one or more bacterial 
species at or above pathological threshold) at baseline (i.e. Visit 1) in the study eye. 
Pathological threshold for individual bacterial species will be based on colony forming unit 
(CFU)/ml threshold levels established by Cagle and modified by Leibowitz (Leibowitz, 1991) 
for different ocular bacterial species found in the specimens collected from each subject as 
specified in Appendix 20.1. 


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5. 
SUBJECT DISPOSITION 
A listing of all Screen Failures (ie, subjects who were screened but not randomized) will be 
presented along with reasons for screen fail.   
The number of subjects included in each subject population (ie, Screened, Safety, ITT and 
mITT) will be summarized by randomized treatment group, age strata and overall except for the 
Screened Set, which will be summarized for all subjects only. 
The number and percentage of subjects who completed and prematurely discontinued during the 
Double-masked Evaluation Phase will be presented for each treatment group, age strata and 
overall.  Reasons for premature discontinuation from the Double-masked Evaluation Phase as 
recorded on the termination page of the eCRF will be summarized (number and percentage) by 
treatment group, age strata and overall.  All percentages will be based on the number of subjects 
in the ITT Population.  
A listing of disposition will be provided for all subjects. All subjects who prematurely 
discontinued during the Double-masked Evaluation Phase will be listed by discontinuation 
reason. 


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6. 
PROTOCOL DEVIATIONS 
Protocol deviations will be recorded by the site monitors separately from the clinical database. 
Protocol deviations will be listed and summarized for subjects in the ITT Population for each 
treatment group by country and overall. Summary tables will be presented with the following 
Clinical Trial Management System (CTMS) categories: 
• Informed Consent 
• Eligibility and Entry Criteria 
• Concomitant Medication Criteria 
• Laboratory Assessment Criteria 
• Study Procedures Criteria 
• Serious Adverse Event Criteria 
• Randomization Criteria 
• Visit Schedule Criteria 
• IP Compliance 
• Efficacy Criteria 
• Administrative Criteria 
• Source Document Criteria 
• Regulatory or Ethics Approvals Criteria 
• Other Criteria 
 
In addition to the 14 CTMS categories, number of subjects in the ITT population for each 
treatment group by country and overall will also be summarized for subjects coming to visits 
who did not have 12 hours since their last dose, which could be mapped to multiple CTMS 
categories.  


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7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for ITT and mITT.  
The following demographic characteristics will be summarized in the following order in the 
tables: age, age strata (< 6 years [0-27 days], 6 to <18 years and ≥18 years), sex, ethnicity and 
race. In addition, iris color in the study eye will be summarized.  
Percentages will be based on the total number of subjects in each treatment group. 
A listing will be generated for demographic and baseline characteristics for the ITT Population. 
Ocular and non-ocular medical history will be descriptively summarized based on the system 
organ class (SOC) and preferred term coded terms (Medical Dictionary for Regulatory Activities 
[MedDRA] version 19.1) by treatment group and overall for the Safety Population. Data 
summaries will be sorted by the overall frequency of reporting within SOC. 
A listing of ocular and non-ocular medical history will be provided for the Safety Population. 


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8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
Exposure to Investigational product  
Exposure to double-masked investigational product for the Safety Population will be 
summarized in terms of treatment duration, which is calculated as the number of days from the 
date of first dose of double-masked investigational product taken to the date of the last dose of 
double-masked investigational product taken, inclusively, and irrespective of any investigational 
product interruption(s).  Descriptive statistics will be presented by treatment group and overall.  
A listing of investigational product exposure will be provided for all subjects in the Safety 
Population. 
8.2 
Measurement of Treatment Compliance 
Investigational product dosing compliance for the double masked treatment period is defined as 
the total number of doses actually taken by a subject during that period divided by the number of 
doses expected to be taken during the same period multiplied by 100.   
For completers (i.e. subjects who completed all 7 days of dosing), the total number of expected 
doses is 28 (i.e. 4 doses per day for 7 days). For subjects who early terminated dosing on Day 1, 
the total number of expected doses is set to be 1. For the rest of subjects who terminated dosing 
before 7 days, the total number of expected doses is the number of full dosing day multiplied by 
4. For example, if a subject early terminates on Day 4, his/her total number of expected doses is 
3 (full dosing day) x 4 (doses per day) = 12. 
At each visit, the number of missed doses or extra doses since last visit will be recorded on the 
CRF. The total number of missed doses will be derived as the sum of the number of missed 
doses since last visit across all visits. The total number of extra doses will be derived as the sum 
of the number of extra doses since last visit across all visits. The total number of doses actually 
taken will be derived as the total number of expected doses plus the total number of extra doses 
minus the total number of missed doses.  
Descriptive statistics [number of subjects (n), mean, median, standard deviation (SD), minimum, 
maximum] for investigational product compliance will be presented by treatment group and 
overall for the whole double-masked evaluation phase for the Safety Population. Number of 
subjects (percentage) who completed 4 days of dosing by Visit 3 with no extra or missed dose 
will also be presented by treatment group and overall for the Safety Population.  
A listing of treatment compliance will be provided for all subjects in the Safety Population. 


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9. 
PRIOR AND CONCOMITANT MEDICATION  
All medications will be coded using the World Health Organization – Drug Dictionary (WHO-
DD) Version 01SEP2016 categorized by anatomical therapeutic class (ATC) and preferred term. 
Medications/therapies/procedures will be further categorized as ocular or non-ocular by the 
investigator based on the indication for which the medication/therapy/procedure was used. 
Prior medication/therapy/procedure is defined as any medication/therapy/procedure with a start 
date prior to the date of the first dose of investigational product.  
Concomitant medication/therapy is defined as any medication/therapy with a start date prior to 
the date of the first dose of investigational product and continuing after the first dose of 
investigational product or with a start date between the dates of the first and last doses of 
investigational product, inclusively. Concomitant procedure is defined as any procedure with a 
start date between the dates of the first and last doses of investigational product, inclusively. Any 
medication/therapy/procedure with a start date after the date of the last dose of investigational 
product will not be considered a concomitant medication/therapy/procedure.  
Both prior and concomitant medication usage will be summarized by the number and proportion 
of subjects receiving each medication within each ATC and each preferred term by treatment 
group and overall for the Safety Population.  Medications can be counted both as prior and 
concomitant medication.  Multiple medication usage by a subject in the same category will be 
counted only once. 
Ocular and non-ocular medications will be summarized separately. 
All prior and concomitant medication will be listed. Prior and concomitant therapy/procedure 
will not be summarized, but will be listed. Imputed dates (see Section 18.6 for imputation rules) 
will be marked in the listings. 
Medication/therapy/procedure with a start date after the date of the last dose of investigational 
product will also be listed.  


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10. EFFICACY ANALYSES 
All efficacy analyses will be based on the mITT unless stated otherwise.  Baseline for all 
efficacy analyses is defined as the value for the efficacy assessment at Visit 1.   
All statistical tests will be 2-sided hypothesis tests performed at the 4.99% level of significance 
for main effects.  All confidence intervals (CIs) will be 2-sided 95% CI, unless stated otherwise.  
All efficacy analyses will be conducted according to the treatment assigned. 
Multiplicity adjustments will be done on the primary and key secondary efficacy endpoints 
testing as described in Section 2.6. 
Missing post-baseline efficacy assessments will be imputed using LOCF from post-baseline 
values and all efficacy statistical inference will be made based on analyses using LOCF, unless 
stated otherwise. If a subject has no post-baseline efficacy assessment then no LOCF will be 
done for that efficacy assessment for the subject. In other words, the subject’s Visit 3 (Day 5) 
data will remain missing which means the subject will be excluded from the primary analysis in 
mITT and sensitivity analysis in ITT for that efficacy assessment. 
All efficacy endpoints will be listed in the ITT Population. The listing will include a flag to 
indicate whether the subject is in mITT. 
10.1 
Study Eye Designation 
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a 
score of at least 1 for both ocular conjunctival discharge and bulbar conjunctival redness at 
baseline: 
• For subjects with both eyes eligible and both with a positive bacterial culture (presence of 1 
or more bacterial species at or above pathological threshold) at baseline or both eyes eligible 
and both with a non-positive bacterial culture (absence of any bacterial species at or above 
pathological threshold) at baseline, the study eye will be the eye with the highest global 
clinical score (refer to Section 3.2) at baseline. If both eyes have the same global clinical 
score at baseline, then the study eye will be the right eye.  
• For subjects with both eyes eligible with a positive bacterial culture in 1 eye at baseline, the 
baseline bacterial culture positive eye will be the study eye.  
• For subjects with only 1 eligible eye, the eligible eye will be the study eye irrespective of its 
baseline bacterial culture result.  
The study eye designation is summarized in the table below: 


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Eligible Eye(s) 
Bacterial Culture Results 
Study Eye 
Both eyes 
Both eyes positive 
Highest global clinical score at Visit 1  
(or right eye if scores are the same) 
Both eyes 
Both eyes negative 
Highest global clinical score at Visit 1  
(or right eye if scores are the same) 
Both eyes 
One eye positive 
The bacterial culture positive eye at Visit 1  
One eye 
Positive or negative for either eye 
The eligible eye  
 
The eye other than the study eye is considered the fellow eye in all safety analyses. 
10.2 
Primary Efficacy Endpoint and Analysis  
The primary efficacy endpoint is clinical resolution status (defined as absence [ie, a score of 0] 
of bulbar conjunctival injection and ocular conjunctival discharge) in the study eye at Visit 3 
(Day 5) between SHP640 and placebo.   
The null hypothesis to be tested is that there is no difference in proportion of subjects with 
clinical resolution in the study eye between SHP640 ophthalmic suspension and placebo with the 
alternative of the non-zero difference in the proportion with clinical resolution between them. 
The proportion of subjects with clinical resolution will be compared between SHP640 and 
placebo groups using two-sided Fisher’s Exact test at two-sided 4.99% level of significance. 
Missing data will be imputed based on post baseline LOCF for the determination of clinical 
resolution in the study eye at Visit 3 (Day 5). The primary basis of inference for this comparison 
will be based on the analysis conducted in mITT. Frequency and percent of subjects who 
reached/did not reach clinical resolution in the study eye at Visit 3 (Day 5) will be reported by 
treatment group along with the two-sided Fisher’s Exact test p value for comparison between 
SHP640 and placebo. The two-sided 95% CI for response rate (exact CI for binominal 
proportion) in each treatment group as well as the estimated difference in response rates and 
corresponding two-sided 95% asymptotic CI for the difference will also be reported.  
Example SAS code for conducting Fisher’s exact test and generating the CIs is in Appendix 
20.2.1. 
10.3 
Sensitivity Analyses for the Primary Efficacy Endpoint 
ITT Population Analysis 
A sensitivity analysis will be conducted by repeating the primary analysis using the ITT 
Population. Frequency and percent of subjects who reached/did not reach clinical resolution in 
the study eye at Visit 3 (Day 5) will be reported by treatment group along with the two-sided 
Fisher’s Exact test p value for comparison between SHP640 and placebo. The two-sided 95% CI 
for response rate (exact CI for binominal proportion) in each treatment group as well as the 
estimated difference in response rates and corresponding two-sided 95% asymptotic CI for the 
difference will also be reported.  


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Missing Data Imputation 
Method 1: Modified Worst Observation Carry Forward (WOCF) 
The between-treatment group comparison (SHP640 versus placebo) for the primary efficacy 
endpoint will be performed using Fisher’s Exact test on the mITT data set. Missing data will be 
imputed based on post baseline WOCF for the determination of clinical resolution in the study 
eye at Visit 3 (Day 5). For clinical resolution status, not reaching clinical resolution is considered 
worse than reaching clinical resolution. If a subject has no post-baseline efficacy assessment up 
to Visit 3 (Day 5), then his/her baseline efficacy assessment will be carried forward as the Visit 3 
(Day 5) assessment.  
Frequency and percent of subjects who reached/did not reach clinical resolution in the study eye 
at Visit 3 (Day 5) in the imputed data set will be reported by treatment group along with the two-
sided Fisher’s Exact test p value for comparison between SHP640 and placebo. The two-sided 
95% CI for response rate (exact CI for binominal proportion) in each treatment group as well as 
the estimated difference in response rates and corresponding two-sided 95% asymptotic CI for 
the difference will also be reported.  
Method 2: Multiple imputations 
Multiple imputation (MI) methods will utilize the SAS procedures PROC MI and PROC 
MIANALYZE in mITT. The MI procedure will first impute the global clinical score (GCS) at 
Visit 3 based on a regression model with treatment, age strata (< 6 years, 6 to <18 years and ≥18 
years) as categorical independent variables and baseline GCS and GCS at Visit 2 as continuous 
independent variable assuming monotone missing pattern. In case the missing pattern is not 
monotone, Markov Chain Monte Carlo (MCMC) multiple imputation will be conducted first to 
impute enough data to produce a monotone missing data pattern. The MI procedure will generate 
10 datasets with missing data imputed. The imputed GCS data will be rounded to integers and 
bounded to 0 to 7 during imputation so that the imputed values match the format of the observed 
values as well as existing range. Once the missing values are imputed and each dataset is created, 
clinical resolution status at Visit 3 will be derived based on the GCS scores at Visit 3. Binomial 
proportion for clinical resolution at Visit 3 in each treatment group, corresponding standard error 
(SE), the difference in the proportions between SHP640 and placebo and SE of the difference 
will be generated in each imputed data set and then appropriately pooled across the multiply 
imputed data sets using PROC MIANALYZE. The pooled binominal proportion point estimate 
in each treatment arm, the two-sided 95% CI for pooled proportion point estimate, the pooled 
point estimate of the difference between proportions in SHP640 and placebo, the corresponding 
p value and two-sided 95% CI will be reported.  
Appendix 20.2.2 shows example SAS code for MI analysis. 


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10.4 
Exploratory Analyses for the Primary Efficacy Endpoint 
Adjusted Chi-square Test 
Since all subjects from the same household will be assigned to the same treatment group, an 
exploratory analysis will be conducted on the primary efficacy endpoint in mITT based on an 
adjusted Chi-square test to account for clustering of the data (Jung et al., 2001). The proportion 
of subjects with clinical resolution in the study eye will be compared between SHP640 
ophthalmic suspension and placebo with missing data imputed with post baseline LOCF for the 
determination of clinical resolution in the study eye at Visit 3 (Day 5). Adjusted Chi-square test 
statistics and corresponding p value will be presented. 
Appendix 20.2.3 shows example SAS code for the adjusted chi-square test. 
Analysis Based on CRF Visits 
Analysis visits in the primary analysis will be derived based on rules specified in Section 18.2 of 
this SAP. An exploratory analysis will be conducted repeating the primary analysis on the 
primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 5) in mITT based 
on CRF recorded Visit 3 data.  Frequency and percent of subjects who reached/did not reach 
clinical resolution in the study eye at Visit 3 will be reported by treatment group along with the 
two-sided Fisher’s Exact test p value for comparison between SHP640 and placebo. The two-
sided 95% CI for response rate (exact CI for binominal proportion) in each treatment group as 
well as the estimated difference in response rates and corresponding two-sided 95% asymptotic 
CI for the difference will also be reported. 
10.5 
Key Secondary Efficacy Endpoints and Analysis  
The key secondary efficacy endpoint of this study is bacterial eradication status (defined as 
absence of all bacterial species present at or above pathological threshold at baseline) in the 
study eye at Visit 3 (Day 5) between SHP640 and placebo. 
The null hypothesis to be tested is that there is no difference in proportion of subjects reaching 
bacterial eradication in the study eye at Visit 3 (Day 5) between SHP640 and placebo with the 
alternative hypothesis of non-zero difference in the proportion of responders between the two 
treatment groups.  
In order to maintain the study-wide Type I error at 5% (two sided alpha of 0.0001 at IA and two 
sided alpha of 0.0499 at final analyses), the primary and key secondary hypotheses will be tested 
sequentially using two-sided Fisher’s exact test with the primary efficacy endpoint being tested 
first and the key secondary efficacy endpoint being tested second. The hypothesis test for the key 
secondary efficacy endpoint will not be performed unless the hypothesis test for the primary 
efficacy endpoint is statistically significant. 
Missing data will be imputed based on the post baseline LOCF for the determination of bacterial 
eradication status in the study eye at Visit 3 (Day 5). The primary basis of inference for the key 
secondary comparison will be based on the analysis conducted in mITT. Frequency and percent 


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of responders in the study eye at Visit 3 (Day 5) will be reported by treatment group along with 
the two-sided Fisher’s Exact test p value for comparison between the two treatment groups. The 
two-sided 95% CI for response rate (exact CI for binominal proportion) in each treatment group 
as well as the estimated difference in response rates and corresponding two-sided 95% 
asymptotic CI for the difference will also be reported. 
Sensitivity and exploratory analyses will also be conducted on key secondary efficacy endpoint 
using the same methods as described in Section 10.3 and 10.4 (i.e. modified WOCF imputation 
and multiple imputation as sensitivity analyses; adjusted Chi-square test and analysis based on 
CRF visits as exploratory analyses) except for the ITT population sensitivity analysis, which will 
not be conducted for bacterial eradication key secondary endpoint.  
In addition, a subgroup analysis will be conducted by repeating the Fisher’s exact test with post 
baseline LOCF for the determination of bacterial eradication status in the study eye at Visit 3 
(Day 5) in the mITT excluding bacterial eradication data obtained from swabs where the last 
dose of study medication was instilled within 12 hours of the swab (i.e. swab occurred <12 hours 
after last dose of investigational product). Frequency and percent of responders in the study eye 
at Visit 3 (Day 5) will be reported by treatment group along with the two-sided Fisher’s Exact 
test p value for comparison between the two treatment groups. The two-sided 95% CI for 
response rate (exact CI for binominal proportion) in each treatment group as well as the 
estimated difference in response rates and corresponding two-sided 95% asymptotic CI for the 
difference will also be reported. This subgroup analysis is not statistically powered. 
10.6 
Other Secondary Efficacy Endpoints and Analysis 
Secondary efficacy endpoints are defined as follows: 
• Clinical resolution status of bacterial conjunctivitis at Visits 2 (Day 3), 4 (Day 8), and 5 
(Day 12) in the study eye 
• Bacterial eradication status (defined as absence of all bacterial species present at or above 
pathological threshold at baseline) as assessed by bacterial culture at Visits 2 (Day 3), 4 (Day 
8), and 5 (Day 12) in the study eye  
• Absolute and change from baseline of the individual clinical signs score (bulbar conjunctival 
injection and ocular conjunctival discharge) at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), and 5 
(Day 12) in the study eye  
• The global clinical score (defined as the sum of bulbar conjunctival injection and ocular 
conjunctival discharge) and change from baseline in the global clinical score at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye  
• Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 5), 4 (Day 8), and 5 (Day 12) in the study eye  
• Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with 
neither injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), 
and 5 (Day 12) in the study eye  


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• Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 5), 4 (Day 8), 
and 5 (Day 12) in the study eye 
• Use of rescue medication 
 
All secondary efficacy analyses will be performed on the mITT and presented by treatment 
group. No hypothesis testing will be conducted for the secondary efficacy endpoints. All 
secondary efficacy endpoints will be summarized by treatment group using descriptive statistics 
at each assessment visit. Continuous endpoints will be summarized by number of subjects (n), 
mean, median, SD, minimum, maximum and two-sided 95% CI. Binary endpoints will be 
summarized by number of subjects (n), frequency, proportion and two-sided 95% CI (exact CI 
for binominal proportion). Time to event endpoint will be summarized by Kaplan-Meier survival 
estimates (number of events, number at risk, survival function at each assessment visit, median 
survival time and 95% CI). Survival plot by treatment group will also be generated. 
Appendix 20.2.4 shows example SAS code for generating descriptive statistics. 
10.7 
Exploratory Efficacy Endpoints and Analyses  
Ocular discomfort associated with conjunctivitis symptoms will be assessed through the Ocular 
Discomfort Scale. The Ocular Discomfort Scale is composed of three items: eye pain, itching, 
and foreign body sensation. The subject will be asked three questions about his/her experience 
with pink eye over the past 24 hours: how bad was your eye pain (for example, a hurting, 
burning, or stinging feeling in your eye) at its worst; how bad was the felling that something was 
in your eye (like an eyelash or dirt) from your pink eye at its worst; how bad was the itching 
from your pink eye at its worst. All questions will be evaluated using a 0-10 scale with 0 
indicating no symptom and higher score indicating more severe symptom. A separate scale will 
be administered for children less than 8 years of age, which has a single question for the parent 
about whether his/her child experienced eye pain or discomfort because of pink eye over the past 
24 hours (child rubbing his/her eyes, crying or tearing up, and/or telling parent that he/she is 
having pain or discomfort) with a Yes/No answer. 
The ocular discomfort endpoints will be collected at Visit 2 (Day 3), Visit 3 (Day 5), Visit 4 
(Day 8), and Visit 5 (Day 12). For the ocular discomfort endpoints obtained from the scale for 
adults and children 8 years and older (individual scores and total score), absolute and change 
from baseline of ocular discomfort scores due to conjunctivitis symptoms will be summarized by 
treatment group at each visit in mITT and ITT population.  
The binary ocular discomfort endpoint obtained from children less than 8 years of age will also 
be summarized by treatment group at each visit in mITT and ITT population. 
No hypothesis testing will be conducted for the exploratory efficacy endpoints. Similar to 
secondary efficacy endpoints, all exploratory efficacy endpoints will be summarized by 
treatment group using descriptive statistics at each assessment visit. Continuous endpoints will 
be summarized by number of subjects (n), mean, median, SD, minimum, maximum and two-
sided 95% CI. Binary endpoints will be summarized by number of subjects (n), frequency, 
proportion and two-sided 95% CI (exact CI for binominal proportion). 


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11. SAFETY ANALYSES 
The safety analysis will be performed using the Safety Population.  Safety variables include 
adverse events (AEs; including local tolerability), slit lamp biomicroscopy, non-dilated/dilated 
fundus exam, red reflex exam, best corrected visual acuity (BCVA), and urine pregnancy testing 
(for females of childbearing potential) variables.  
Safety data collected at baseline (Visit 1) will be used as the baseline value for safety analysis.  
All safety analyses will be conducted according to the treatment the subject actually received.  
11.1 
Adverse Events  
AEs will be coded using MedDRA version 19.1. Any AE that occurs after the first dose of 
investigational product instillation will be considered a treatment-emergent adverse event 
(TEAE). 
An overall summary of the number of subjects with TEAEs will be presented, including the 
number and percentage of subjects with any TEAEs, ocular TEAEs, non-ocular TEAEs, TEAEs 
leading to death, serious TEAEs, TEAEs related to investigational product and TEAEs leading to 
discontinuation of investigational product as well as the total number of events in each category. 
The number and percentage of subjects reporting TEAEs in each treatment group and across all 
subjects will be tabulated by SOC and preferred term as well as by SOC, preferred term, and 
maximum severity.  TEAEs considered related to investigational product will also be 
summarized by SOC and preferred term. If more than 1 AE occurs with the same SOC/preferred 
term for the same subject, then the subject will be counted only once for that SOC/preferred term 
using the most severe and most related occurrence for the summarization by severity and by 
relationship to investigational product, respectively. The incidence of common TEAEs (≥ 5% of 
subjects in any treatment group) will also be summarized by SOC and preferred term. Serious 
TEAEs, TEAEs leading to discontinuation of investigational product and TEAEs leading to 
death, will be summarized by SOC, preferred term and treatment group and across all subjects. 
The number and percentage of subjects reporting local tolerability TEAEs in each treatment 
group and across all subjects will also be tabulated. Local tolerability TEAEs (overall, related to 
IP and not related to IP) will be tabulated by SOC and preferred term. Preferred terms that are 
considered to be local tolerability AEs will be provided by global drug safety (GDS) before 
database lock. Separate tables will be generated for ocular TEAEs and non-ocular TEAEs. For 
all above tables, ocular TEAEs will be summarized at subject level and also by study eye, fellow 
eye and both eyes.  
Listings of all TEAEs will be provided by subject.  
Pre-treatment events (captured on the AE form that occurred prior to the first dose of 
investigational product) will be listed by subject but not tabulated. 
Imputed dates, severity and relationship to investigational product (see Section 18.7, 18.8 and 
18.9 respectively for imputation rules) will be marked in the listings. 


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11.2 
Other Safety Variables 
The following safety measures will be descriptively summarized by study eye and fellow eye and 
by treatment group and across all subjects at each visit: 
• Best corrected visual acuity (BCVA, logMAR scoring) and change from baseline BCVA 
• Slit lamp biomicroscopy (normal, abnormal – not clinically significant, abnormal – 
clinically significant) for 6 anatomic anterior segment regions: lids, conjunctiva, cornea, 
iris, anterior chamber and lens  
• Non-dilated/ Dilated Fundus examination (normal, abnormal – not clinically significant, 
abnormal – clinically significant) for 3 anatomic posterior segment regions: vitreous,  
optic nerve and macula 
• Red reflex examination (normal, abnormal– not clinically significant, abnormal – 
clinically significant) for infants and small children in whom a fundus examination 
cannot be done 
Continuous endpoints will be summarized by number of subjects (n), mean, median, SD, SE, 
minimum and maximum. Binary endpoints will be summarized by number of subjects (n), 
frequency and percentage. 
BCVA/change from baseline BCVA and slit lamp biomicroscopy at each visit as well as non-
dilated/ dilated fundus examination (or red reflex exam for infants and small children in whom a 
fundus examination cannot be done), and pregnancy test results at visits 1 and 5/early 
termination will be provided by subject in Safety Population in data listings. A by subject listing 
will also be generated for chlamydia and gonorrhea results at Visit 1 in Safety Population in 
subjects less than 2 month of age and for Herpes Simplex Virus (HSV) at Visit 1 in Safety 
Population. 


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12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable. 


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13. OTHER ANALYSES  
Subgroup analyses will be performed on the primary and key secondary efficacy endpoint. The 
following subgroups will be used: age stratum (< 6 years, 6 to <18 years, ≥18 years and overall 
pediatric group, i.e. <18 years), gender, race, ethnicity, iris color of the study eye and region. The 
planned regions and countries are: North America (Canada and United States including Puerto 
Rico), South America (Colombia, Peru), Asia-Pacific (Australia, India and Philippines), Europe 
(Austria, Estonia, France, Germany, Hungary, Italy, Poland, Spain and United Kingdom) and 
Middle East/Africa (Israel, South Africa). Descriptive statistics (number of subjects [n], 
frequency, proportion, two-sided 95% exact CI for binominal proportion) will be generated for 
the primary and key secondary efficacy endpoints by treatment group in mITT. Pairwise 
difference in response rates and corresponding two-sided 95% asymptotic CI for the difference 
will also be generated in mITT. No hypothesis testing will be conducted as the study is not 
powered to detect treatment effect within subgroups.      


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14. INTERIM ANALYSIS 
An unmasked IA will be performed after ~50% subjects exit the trial in the mITT population, 
with data to be analyzed entered into the database, queried, and discrepancies resolved. The 
purpose of the IA will be to assess the adequacy of the initial sample size estimation by 
evaluating conditional power for the primary comparison of SHP640 versus placebo on clinical 
resolution in the treatment of subjects with bacterial conjunctivitis in the study eye at Visit 3 
(Day 5). There is no intention to stop early for efficacy or futility based on the results from the 
IA.  
The IA will be performed by an external unmasked independent statistician and/or unmasked 
programmers based on a prespecified interim SAP. The interim SAP will explicitly describe how 
the conditional power is to be calculated and the precise rules for altering the sample size 
depending on the potential results. The interim SAP will be finalized prior to IA. The interim 
statistical report including the results will be distributed only to a limited group of people who 
are not involved in the conduct of the trial. All sponsor, CRO, and site staff involved in the 
conduct of the trial must remain masked throughout the trial. Recommendation from the IA to 
increase the sample size may require an amendment to the study protocol. There is no inflation 
of type I error from this IA because the sole purpose of the planned IA is to adjust the sample 
size by using the conditional power approach, and the sample size will be changed only under 
certain conditions (Mehta and Pocock, 2011). However, for conservativeness, two sided 0.0001 
alpha will be spent for the proposed IA and a two sided alpha of 0.0499 will be used for final 
analyses. 


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15. DATA MONITORING/REVIEW COMMITTEE 
There is no data monitoring committee for this study.  


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16. COMPUTER METHODS  
Statistical analyses will be performed using Version 9.2 (or higher) of SAS on a suitably 
qualified environment.   


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17. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Change from baseline BCVA has been added in Section 11.2, other safety variables. 


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18. DATA HANDLING CONVENTIONS 
18.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics: number of 
subjects (n), mean, median, SD, minimum, maximum unless otherwise specified.  Categorical 
and count variables will be summarized by the number of subjects (n), frequency and the percent 
of subjects in each category unless otherwise specified.  Percentages will be presented with one 
decimal point.  
See TFLs4Shire for rules on the number of decimal places to present data and p-values.  
18.2 
Study Visits and Windows 
Assessments will be assigned to visits based upon the date the assessment took place regardless 
of the CRF page completed. Assessments will be mapped to visits as outlined in Table 2. 
Should there be more than 1 assessment mapped into a given study visit, the assessment closest 
to the planned visit will be used for analysis (referred to as analysis visit); if equally close, 
choose assessment obtained on the scheduled visit or the last assessment if there is no data on the 
scheduled visit. 
Study day will be calculated as follows: 
• If the assessment date is on or after the date of first instillation:  
Study day = assessment date – first dosing date + 1 
• If the assessment date is before the date of first instillation: 
Study day = assessment date – first dosing date 
Table 2:  Visit Windows (Study Day Based) 
Visit 
Planned Study Day 
Start Day of Window 
End Day of Window 
Visit 1 (Screening & 
Baseline) 
1 
Date of CRF Visit 1 
1 
Visit 2 
3 
3 
4 
Visit 3 
5 
5 
6 
Visit 4 
8 
8 
9 
Visit 5 
12 
12 
14 


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18.3 
Derived Efficacy Endpoints  
Clinical resolution is defined as absence of bulbar conjunctival injection and ocular conjunctival 
discharge. Bulbar Conjunctival Injection will be assessed based on a 0-4 scale which uses 
pictures from the Validated Bulbar Redness (VBR) Scale. Ocular Conjunctival Discharge will be 
assessed based on a 0-3 scale. For both bulbar conjunctival injection and ocular conjunctival 
discharge, 0 score indicates normal or none and a higher score indicates a higher severity of the 
clinical sign. A 0 sum of bulbar conjunctival injection score and ocular conjunctival discharge 
score represents reaching clinical resolution. Any non 0 sum means not reaching clinical 
resolution. If either individual score is missing, clinical resolution status will be set to missing. 
Bacterial eradication is defined as absence of all bacterial species present at or above 
pathological threshold at baseline (see Appendix 20.1 for pathological thresholds). Presence of at 
least one bacterial species that were at or above pathological threshold at baseline is considered 
not reaching bacterial eradication. If an eye has missing bacterial culture result at baseline, the 
eye will be assumed to be bacterial culture negative at baseline for determination of the study 
eye. 
Global clinical score is defined as the sum of bulbar conjunctival injection score and ocular 
conjunctival discharge score. If either individual score is missing, global clinical score will be set 
to missing. 
Modified clinical resolution is defined as a global clinical score of 0 or 1. All other scores are 
considered not reaching modified clinical resolution. If either individual score is missing, 
modified clinical resolution status will be set to missing. 
Expanded clinical resolution is defined as a global clinical score of 0, 1, or 2 with neither bulbar 
conjunctival injection score nor ocular conjunctival discharge score having a score of 2. 
Otherwise, the subject is considered not reaching expanded clinical resolution. If either 
individual score is missing, expanded clinical resolution status will be set to missing. 
Time to clinical resolution will be derived based upon assessments at Visits 2 (Day 3), 3 (Day 5), 
4 (Day 8), and 5 (Day 12) in the study eye. Time to clinical resolution will equal to the study day 
corresponding to the visit when the subject first reaches clinical resolution in the study eye. 
Ocular discomfort total score (in the version for adult and older children) is defined as the sum of 
eye pain score, the feeling that something was in your eye score and itching score. If any 
individual score is missing, then ocular discomfort total score will be set to missing. 
18.4 
Repeated or Unscheduled Assessments of Safety Parameters  
Assessments will be mapped to analysis visit according to rules specified in Section 18.2. 
Additional repeated or unscheduled assessments will not be included in the by visit summary 
tables, but will be included in subject listings. Assessments that were not mapped to any analysis 
window (including repeated or unscheduled assessments) will be included in LOCF and 
modified WOCF imputation and subject listings. 


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18.5 
Missing Date of Investigational Product  
When the date of the last dose of investigational product is missing for a subject in the Safety 
Population, all efforts should be made to obtain the date from the investigator.  If it is still 
missing after all efforts, then the last visit date when investigational product was returned will be 
used in the calculation of treatment duration.   
18.6 
Missing Date Information for Prior or Concomitant Medications  
For prior or concomitant medications, including rescue medications, incomplete (ie, partially 
missing) start date and/or stop date will be imputed.  When the start date and the stop date are 
both incomplete for a subject, impute the start date first.     
18.6.1 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields.  If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing day and month 
• 
If the year of the incomplete start date is the same as the year of the date of the first dose of 
investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields 
• 
If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields 
• 
If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
• 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
• 
If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of investigational product, then the day of the date of the first dose of 
investigational product will be assigned to the missing day 
• 
If either the year is before the year of the date of the first dose of investigational product or 
if both years are the same but the month is before the month of the date of the first dose of 
investigational product, then the last day of the month will be assigned to the missing day 
• 
If either the year is after the year of the date of the first dose of investigational product or if 
both years are the same but the month is after the month of the date of the first dose of 
investigational product, then the first day of the month will be assigned to the missing day.  


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18.6.2 
Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields.  If the date of the last 
dose of investigational product is missing, then replace it with the last visit date.  If the imputed 
stop date is before the start date (imputed or non-imputed start date), then the imputed stop date 
will be equal to the start date. 
Missing day and month 
• 
If the year of the incomplete stop date is the same as the year as of the date of the last dose 
of investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields 
• 
If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields 
• 
If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
• 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
• 
If the month and year of the incomplete stop date are the same as the month and year of the 
date of the last dose of investigational product, then the day of the date of the last dose of 
investigational product will be assigned to the missing day 
• 
If either the year is before the year of the date of the last dose of investigational product or 
if both years are the same but the month is before the month of the date of the last dose of 
investigational product, then the last day of the month will be assigned to the missing day 
• If either the year is after the year of the last dose of investigational product or if both years 
are the same but the month is after the month of the date of the last dose of investigational 
product, then the first day of the month will be assigned to the missing day. 
18.7 
Missing Date Information for Adverse Events  
For AEs, incomplete (i.e. partially missing) start dates will be imputed if the subject is missing 
whether the event occurred prior to the first study drug dose. Incomplete stop dates will not be 
imputed.  
18.7.1 
Incomplete Start Date  
If incomplete state date needs to be imputed, then follow same rules as in Section 18.6.1. 


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18.8 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned.  If the severity is missing for an AE starting 
after the first dose of investigational product, then a severity of “Severe” will be assigned.  The 
imputed values for severity assessment will be used for incidence summaries, while both the 
actual and imputed values will be used in data listings. 
18.9 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting after the first dose of 
investigational product, a causality of “Related” will be assigned.  The imputed values for 
relationship to double-masked investigational product will be used for incidence summaries, 
while both the actual and imputed values will be presented in data listings. 


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19. REFERENCES 
Jung, S.-H., Ahn, C.and Donner, A. 2001. Evaluation of an adjusted chi-square statistic as 
applied to observational studies involving clustered binary data. Statistics in Medicine, 
20, 2149-2161. 
Leibowitz, H. M. 1991. Antibacterial effectiveness of ciprofloxacin 0.3% ophthalmic solution in 
the treatment of bacterial conjunctivitis. American Journal of Ophthalmology, 112, 29S-
33S. 
Mehta, C. R.and Pocock, S. J. 2011. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Statistics in medicine, 30, 3267-84. 
Pocock, S. J.and Simon, R. 1975. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 31, 103-15. 


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20. APPENDIX 
20.1 
Threshold Criteria for Judging Culture Positive Specimens 
Threshold criteria for judging culture positive specimens* 
Group I – Threshold = 1 CFU/ml 
    Streptococcus, Group A, beta hemolytic (St. pyogenes) 
    St. pneumoniae 
    Citrobacter sp. 
    Enterobacter sp. 
    Escherichia sp. 
    Klebsiella sp. 
    Proteus/Morganella sp. 
    Serratia Marcescens 
    Other Enterobacteriaceae 
    N.gonorrhoeae 
    Other Neisseria sp. 
    Other Moraxella sp. 
    Acinetobacter sp. 
    Achromobacter sp. 
    Haemophilus sp. 
    Pseudomonas aeruginosa 
    Other Pseudomonas sp. 
Group II – Threshold = 10 CFU/ml 
    Staphylococcus aureus 
    Streptococcus Group B (beta or nonhemolytic) 
    Streptococcus Group C (alpha, beta, or nonhemolytic) 
    Other Streptococcus (Groups D, G; nongrouped; viridans) 
    Moraxella (Branhamella) catarrhalis 
Group III – Threshold = 100 CFU/ml 
    S. epidermidis 
    Other coagulase-negative Staphylococcus sp. 
    Micrococcus sp. 
    Bacillus sp. 
Group IV – Threshold == 1000 CFU/ml 
    Corynebacterium (diphtheroids) 
*An ocular specimen will be considered culture-positive if the colony count equalled or exceeded the threshold value.  
 


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Bacterial isolates that are not specified or otherwise covered in the table above (from Leibowitz, 
1991) will be assigned threshold criteria (i.e., assigned to either of groups I to IV) as below: 
1. 
Phylum Actinobacteria  
a. Gram positive bacilli or coccobacilli will be assigned to group IV.  
b. Gram positive cocci will be assigned to group III.  
 
2. 
Phylum Firmicutes  
a. Gram positive isolates will be assigned to group III, except known pathogens 
which may be assigned to either group I (eg, B. anthracis) or group II (eg, 
clostridium perfringens)    
 
3. 
Phylum Proteobacteria  
a. Gram negative isolates will be assigned to group I, except M. catarrhalis which is 
assigned to group II.  
 
4. 
Other 
a. Gram negative isolates belonging to Phylum Bacteroidetes will be assigned to 
group I.  
Note: All group assignments, including for any species that may not be covered by the above 
schemes, will be made prior to final database lock.  
20.2 
Example SAS Code 
20.2.1 
Example SAS Code for Fisher’s Exact Test and the CIs  
Example SAS code for conducting Fisher’s Exact Test is as follows 
proc freq data = testData_SHP640_PBO; 
tables treatment*CS / chisq nocol nopercent; 
run; 
Example SAS code for generating exact CI for binominal proportion is as follows: 
proc freq data = testData_SHP640_PBO; 
tables CS / binomial (exact level='Yes') alpha=0.05; 
by treatment; 
run; 
Example SAS code for generating the estimated difference in response rates and corresponding 
95% asymptotic CI for the difference.  
proc freq data = testData_SHP640_PBO; 
tables treatment*CS / nocol nopercent cl riskdiff alpha=0.05; 
run; 


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20.2.2 
Example SAS Code for Multiple Imputation 
*First generate enough data to produce a monotone missing data pattern; 
*Only include SHP640 and placebo arm in this imputation; 
*MCMC does not work with class statement. Age has been converted to an 
indicator variable; 
*For <6 year old, age1=0 and age2=0, for 6-18 year old, age1=1 and age2=0,  
for >18 year old, age1=0 and age2=1; 
*all variables are rounded to integers. Age1, age2, and trt are bounded to 0 
to 1, GCS_V2 and GCS_V3 are bounded to 0 to 7; 
*Since bacterial eradication is a binary endpoint, the max bound for 
bacterial eradication will be 1 instead of 7; 
proc mi data = testIM3 seed =188 out = impOne NIMPUTE=10 round =  1 1 1 1 1 1 
min =  0 0 0 0 0 0 max =  1 1 1 7 7 7; 
mcmc impute = monotone; 
var trt age1 age2 GCS_BASE GCS_V2 GCS_V3; 
run; 
 
*Full imputation based on a regression model assuming monotone missing 
pattern; 
*All missing treatment and age should have been imputed in MCMC step; 
*Use an indicator variable for age to avoid warning message; 
proc mi data = impOne seed = 321 out = impFinal NIMPUTE = 1 round =  1 1 1 1 
1 1 min =  0 0 0 0 0 0 max =  1 1 1 7 7 7; 
var trt age1 age2 GCS_BASE GCS_V2 GCS_V3; 
monotone regression (GCS_V3 = trt age1 age2 GCS_BASE GCS_V2); 
run; 
 
*Convert GCS to clinical resolution; 
data impFinal1; 
set impFinal; 
if (GCS_V3 = 0) then CS_V3 = 'Yes'; 
else CS_V3 = 'No'; 
run; 
 
*Generate exact binomial proportions in imputed data set; 
proc freq data = impFinal1; 
tables CS_V3 / binomial (exact level='Yes') alpha=0.05; 
by _IMPUTATION_ TREATMENT; 
ods output BINOMIALPROP=prop; 
run; 
 
*create a dataset with estimated proportion of responders in each treatment 
arm and their SE; 
data prop_trt; 
merge prop(where=(LABEL1='Proportion') keep = _IMPUTATION_ TREATMENT NVALUE1 
LABEL1 rename=(NVALUE1=proportion)) 
 
  prop(where=(LABEL1='ASE') keep = _IMPUTATION_ TREATMENT NVALUE1 
LABEL1 rename=(NVALUE1=prop_se)); 
by IMPUTATION_ TREATMENT; 
run; 
 
*Combine proportion estimates; 
proc mianalyze data = prop_trt; 
modeleffects proportion; 
stderr prop_se; 


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by treatment; 
run; 
 
*compute estimates of the difference in proportions between SHP640 and 
placebo and the corresponding SE; 
data trt_diff_640_pbo; 
merge prop_trt(where=(TREATMENT='SHP640') rename=(PROPORTION=prop_640 
PROP_SE=prop_640_SE)) 
 
  prop_trt(where=(TREATMENT='Placebo') rename=(PROPORTION=prop_pbo 
PROP_SE=prop_pbo_SE)); 
by IMPUTATION_; 
run; 
 
data trt_diff_640_pbo1; 
set trt_diff_640_pbo; 
diff_640_pbo = prop_640 - prop_pbo; 
se diff_640_pbo = sqrt(prop_640_SE*prop_640_SE + prop_pbo_SE*prop_pbo_SE); 
run; 
 
 
*Combine proportion difference estimates; 
proc mianalyze data = trt_diff_640_pbo1; 
modeleffects diff_640_pbo; 
stderr se_diff_640_pbo; 
run; 


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20.2.3 
Example SAS Code for Adjusted Chi-square Test 
proc freq data = CSdata1; 
tables treatment*CS / nocol nopercent; 
ods output CrossTabFreqs = CrossTabFreqs (drop = TABLE _TYPE_ _TABLE_ 
ROWPERCENT MISSING); 
run; 
 
data param (drop = TREATMENT CS); 
merge CrossTabFreqs(where=(TREATMENT='640' and CS='Yes') 
rename=(FREQUENCY=y_640)) 
 
  CrossTabFreqs(where=(TREATMENT='PBO' and CS='Yes') 
rename=(FREQUENCY=y_pbo)) 
 
  CrossTabFreqs(where=(TREATMENT='640' and CS='') 
rename=(FREQUENCY=M_640)) 
 
  CrossTabFreqs(where=(TREATMENT='PBO' and CS='') 
rename=(FREQUENCY=M_pbo)) 
 
  CrossTabFreqs(where=(TREATMENT='' and CS='') rename=(FREQUENCY=M)); 
run; 
 
data param1; 
label y_640 = 'y_640'; 
label y_pbo = 'y_pbo'; 
label M_640 = 'M_640'; 
label M_pbo = 'M_pbo'; 
label M = 'M'; 
set param; 
*p is the response rate across the two treatment arms; 
p=(y 640+y_pbo)/M; 
q=1.0-p; 
*Derive X 1^2 and X 2^2; 
x 640 = (y 640-M 640*p)**2/(M 640*p)+(M 640-y 640-M 640*q)**2/(M 640*q); 
x_pbo = (y_pbo-M_pbo*p)**2/(M_pbo*p)+(M_pbo-y_pbo-M_pbo*q)**2/(M_pbo*q); 
*Derive the response rates in the two treatment arms; 
p_640 = y_640/M_640; 
p_pbo = y_pbo/M_pbo; 
run; 
 
proc sort data = CSdata1; 
by treatment; 
run; 
 
proc freq data = CSdata1; 
tables HOUSEID*CS / nocol nopercent; 
by treatment; 
ods output CrossTabFreqs = CrossTabFreqs1 (drop = TABLE _TYPE_ _TABLE_ 
ROWPERCENT MISSING); 
run; 
 
 
data CrossTabFreqs2; 
set CrossTabFreqs1; 
if (HOUSEID >= 1 and CS='') then CS = 'All'; 
if (HOUSEID=.) then delete;  
run; 
 


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proc sort data = CrossTabFreqs2; 
by TREATMENT HOUSEID; 
run; 
 
*y_house is the number of responders in each household, m_house is the total 
number of subjects in each household; 
proc transpose data = CrossTabFreqs2 out = param2 (rename=(YES=y_house 
ALL=m_house)); 
var FREQUENCY; 
id CS; 
by TREATMENT HOUSEID; 
run; 
 
proc sort data = CSdata1 out = CSdata2 nodupkey; 
by HOUSEID; 
run; 
 
proc freq data = CSdata2; 
tables treatment; 
ods output OneWayFreqs = OneWayFreqs (keep = TREATMENT FREQUENCY); 
run; 
 
*n_640 is the total number of household in 640 arm; 
*n_pbo is the total number of household in Placebo arm; 
*n is the total number of household across the two arms; 
data param3 (drop = treatment); 
merge param1 
 
  OneWayFreqs(where=(TREATMENT='640') rename=(FREQUENCY=n_640)) 
 
  OneWayFreqs(where=(TREATMENT='PBO') rename=(FREQUENCY=n_pbo)); 
n = n_640 + n_pbo; 
run; 
 
data param4; 
set param3; 
do houseid = 1 to n; 
 
output; 
end; 
run; 
 
proc sort data = param2; 
by houseid; 
run; 
 
proc sort data = param4; 
by houseid; 
run; 
 
data combined (drop = _NAME_ _LABEL_ NO); 
merge param2 param4; 
by houseid; 
run; 
 
data combined1; 
set combined; 
*p_house is p_ki in the paper, which is the response rate within household i 
in treatment k; 


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p_house = Y_HOUSE/M_HOUSE; 
*Derive MSC within each household; 
if (TREATMENT = '640') then MSC = M_HOUSE*((p_house-p_640)**2)/(n-2.0);  
else if (TREATMENT = 'PBO') then MSC = M_HOUSE*((p_house-p_pbo)**2)/(n-2.0); 
*Derive MSE within each household; 
MSE = Y_house*(1.0-p_house)/(M-n); 
*Derive M k^-1*m ki^2; 
if (TREATMENT = '640') then m tilda temp = (m house**2)/M 640; 
else if (TREATMENT = 'PBO') then m_tilda_temp = (m_house**2)/M_pbo; 
run; 
 
proc means data = combined1 sum; 
var MSC MSE m_tilda_temp; 
ods output summary = stats; 
run; 
 
data stats1 (drop = VNAME_MSC VNAME_MSE VNAME_M_TILDA_TEMP); 
label MSC_SUM = 'MSC_SUM'; 
label MSE_SUM = 'MSE_SUM'; 
label M_TILDA_TEMP_SUM = 'M_TILDA_TEMP_SUM'; 
set stats; 
run; 
 
proc sort data = combined1; 
by treatment; 
run; 
 
*Need to sum up m_ki^2/M_k separately within treatment k; 
proc means data = combined1 sum; 
var m_tilda_temp; 
by treatment; 
output out = stats2 (drop = _TYPE_ _FREQ_) sum = sum; 
run; 
 
proc transpose data = stats2 out = stats3; 
var SUM; 
id TREATMENT; 
run; 
 
data stats4 (rename =(_640=C_temp_640 PBO = C_temp_pbo)); 
set stats3; 
drop _NAME_; 
run; 
 
data finalStats; 
merge param3 stats1 stats4; 
run; 
 
data finalStats1; 
set finalStats; 
m_tilda = (M - M_TILDA_TEMP_SUM)/(n-2.0); 
rho = (MSC_SUM - MSE_SUM)/(MSC_SUM+(m_tilda-1.0)*MSE_SUM); 
C_640 = 1.0 + (C_temp_640-1.0)*rho; 
C_pbo = 1.0 + (C_temp_pbo-1.0)*rho; 
adj_chi_square = X_640/C_640 + X_PBO/C_pbo; 


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*The adjusted chi square statistic follows a Chi-Square distribution with 
df=1; 
p_value = 1.0-probchi(adj_chi_square, 1); 
run; 
 
proc print data = finalStats1; 
var adj_chi_square p_value; 
title 'Adjusted Chi Square Restult'; 
run; 
20.2.4 
Example SAS Code for Generating Descriptive Statistics  
*For binary endpoint; 
proc freq data = testData; 
tables binary_endpoint / binomial (exact level='Yes') alpha=0.05; 
by visit treatment; 
run; 
 
*For continuous endpoint; 
proc means data = testData alpha = 0.05 n mean median std min max clm; 
var continuous_endpoint; 
by visit treatment; 
run; 
 
*For time to event endpoint; 
proc lifetest data= testData atrisk plots=survival(atrisk); 
time timeToCS*censor(0); 
strata treatment; 
run; 


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21. TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS 
Table 
Title 
14.1.1.1 
Subject Disposition (Screened Population) 
14.1.1.2 
Subject Disposition by Age Strata (Screened Population) 
14.1.2.1.1 
Demographics (ITT Population) 
14.1.2.1.2 
Demographics (mITT Population) 
14.1.2.3.1 
Ocular Medical History (Safety Population) 
14.1.2.3.2 
Non-Ocular Medical History (Safety Population) 
14.1.3.1.1 
Prior Ocular Medications (Safety Population) 
14.1.3.1.2 
Prior Non-Ocular Medications (Safety Population) 
14.1.3.2.1 
Concomitant Ocular Medications (Safety Population) 
14.1.3.2.2 
Concomitant Non-Ocular Medications (Safety Population) 
14.1.5.1 
Protocol Deviations (ITT Population) 
14.1.5.2 
Protocol Deviations by Country and Treatment Group (ITT Population) 
14.2.1.1.1 
Primary Endpoint: Primary Endpoint: Comparison of SHP640 versus 
Placebo on Clinical Resolution in Study Eye at Visit 3 (Day 5) with 
LOCF  (mITT Population) 
14.2.1.1.2 
Key Secondary Endpoint: Comparison of SHP640 versus Placebo on 
Bacterial Eradication in Study Eye at Visit 3 (Day 5) with LOCF  (mITT 
Population) 
14.2.1.2.1.1 
Primary Endpoint: Comparison of SHP640 versus Placebo on Clinical 
Resolution in Study Eye at Visit 3 (Day 5)  with LOCF (Sensitivity 
Analysis)  (ITT Population) 
14.2.1.2.1.2 
Primary Endpoint: Comparison of SHP640 versus Placebo on Clinical 
Resolution in Study Eye at Visit 3 (Day 5)  with Modified WOCF 
(Sensitivity Analysis) (mITT Population) 
14.2.1.2.1.3 
Primary Endpoint: Comparison of SHP640 versus Placebo on Clinical 
Resolution in Study Eye at Visit 3 (Day 5)  with Multiple Imputation 
(Sensitivity Analysis)  (mITT Population) 
14.2.1.2.2.1 
Key Secondary Endpoint: Comparison of SHP640 versus Placebo on 
Bacterial Eradication in Study Eye at Visit 3 (Day 5)  with Modified 
WOCF (Sensitivity Analysis)  (mITT Population) 


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Table 
Title 
14.2.1.2.2.2 
Key Secondary Endpoint: Comparison of SHP640 versus Placebo on 
Bacterial Eradication in Study Eye at Visit 3 (Day 5)  with Multiple 
Imputation (Sensitivity Analysis)  (mITT Population) 
14.2.1.3.1.1 
Primary Endpoint: Comparison of SHP640 versus Placebo on Clinical 
Resolution in Study Eye at Visit 3 (Day 5)  with LOCF – Adjusted Chi-
Square Test (Exploratory Analysis)  (mITT Population) 
14.2.1.3.1.2 
Primary Endpoint: Comparison of SHP640 versus Placebo on Clinical 
Resolution in Study Eye at Visit 3 (Day 5)  with LOCF – Analysis Based 
on eCRF Visits (Exploratory Analysis)  (mITT Population) 
14.2.1.3.2.1 
Key Secondary Endpoint: Comparison of SHP640 versus Placebo on 
Bacterial Eradication in Study Eye at Visit 3 (Day 5)  with LOCF - 
Adjusted Chi-Square Test (Exploratory Analysis)  (mITT Population) 
14.2.1.3.2.2 
Key Secondary Endpoint: Comparison of SHP640 versus Placebo on 
Bacterial Eradication in Study Eye at Visit 3 (Day 5)  with LOCF – 
Analysis Based on eCRF Visits (Exploratory Analysis)  (mITT 
Population) 
14.2.1.3.2.3   
Key Secondary Endpoint: Comparison of SHP640 versus Placebo on 
Bacterial Eradication in Study Eye at Visit 3 (Day 5)  with LOCF – 
Excluding Data Obtained where Swab Occurred <12 Hours after Last 
Dose of Investigational Product (Exploratory Analysis)  (mITT 
Population) 
14.2.1.4.1.1 
Clinical Resolution in Study Eye at Visit 3 (Day 5) by Age Stratum 
(Subgroup Analysis)  (mITT Population) 
14.2.1.4.1.2 
Clinical Resolution in Study Eye at Visit 3 (Day 5)  by Gender (Subgroup 
Analysis)  (mITT Population) 
14.2.1.4.1.3 
Clinical Resolution in Study Eye at Visit 3 (Day 5)  by Race (Subgroup 
Analysis)  (mITT Population) 
14.2.1.4.1.4 
Clinical Resolution in Study Eye at Visit 3 (Day 5)  by Ethnicity 
(Subgroup Analysis)  (mITT Population) 
14.2.1.4.1.5 
Clinical Resolution in Study Eye at Visit 3 (Day 5)  by Iris Color of the 
Study Eye (Subgroup Analysis)  (mITT Population) 
14.2.1.4.1.6 
Clinical Resolution in Study Eye at Visit 3 (Day 5)  by Region (Subgroup 
Analysis)  (mITT Population) 
14.2.1.4.2.1 
Bacterial Eradication in Study Eye at Visit 3 (Day 5) by Age Stratum 
(Subgroup Analysis)  (mITT Population) 
14.2.1.4.2.2 
Bacterial Eradication in Study Eye at Visit 3 (Day 5) by Gender 
(Subgroup Analysis)  (mITT Population) 
14.2.1.4.2.3 
Bacterial Eradication in Study Eye at Visit 3 (Day 5) by Race (Subgroup 
Analysis)  (mITT Population) 
14.2.1.4.2.4 
Bacterial Eradication in Study Eye at Visit 3 (Day 5) by Ethnicity 
(Subgroup Analysis)  (mITT Population) 
14.2.1.4.2.5 
Bacterial Eradication in Study Eye at Visit 3 (Day 5) by Iris Color of the 
Study Eye (Subgroup Analysis)  (mITT Population) 


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Table 
Title 
14.2.1.4.2.6 
Bacterial Eradication in Study Eye at Visit 3 (Day 5) by Region 
(Subgroup Analysis)  (mITT Population) 
14.2.2.1.1 
Other Secondary Endpoints: Clinical Resolution in Study Eye by Visit 
(mITT Population) 
14.2.2.1.2 
Other Secondary Endpoints: Bacterial Eradication in Study Eye by Visit  
(mITT Population) 
14.2.2.1.3 
Other Secondary Endpoints: Absolute Score and Change from Baseline in 
Bulbar Conjunctival Injection Evaluation in Study Eye by Visit (mITT 
Population) 
14.2.2.1.4 
Other Secondary Endpoints: Absolute Score and Change from Baseline in 
Ocular Conjunctival Discharge Evaluation in Study Eye by Visit  (mITT 
Population) 
14.2.2.1.5 
Other Secondary Endpoints: Absolute Score and Change from Baseline in 
Global Clinical Score in Study Eye by Visit (mITT Population) 
14.2.2.1.6 
Other Secondary Endpoints: Modified Clinical Resolution in Study Eye 
by Visit (mITT Population) 
14.2.2.1.7 
Other Secondary Endpoints: Expanded Clinical Resolution in Study Eye 
by Visit (mITT Population) 
14.2.2.1.8 
Other Secondary Endpoints: Time to Clinical Resolution (days) in Study 
Eye (mITT Population) 
14.2.2.1.10  
Other Secondary Endpoints: Use of Rescue Medication during the Course 
of the Study Post Randomization  (mITT Population) 
14.2.4.1.1.1 
Exploratory Endpoints: Absolute Score and Change from Baseline in 
Ocular Discomfort by Visit - Pain Score  (mITT Population - Adults and 
Older Children (≥ 8 years)) 
14.2.4.1.1.2 
Exploratory Endpoints: Absolute Score and Change from Baseline in 
Ocular Discomfort by Visit - Pain Score  (ITT Population - Adults and 
Older Children (≥ 8 years)) 
14.2.4.1.2.1 
Exploratory Endpoints: Absolute Value and Change from Baseline in 
Ocular Discomfort by Visit – Foreign Body Sensation Score (mITT 
Population– Adults and Older Children (≥ 8 years)) 
14.2.4.1.2.2 
Exploratory Endpoints: Absolute Value and Change from Baseline in 
Ocular Discomfort by Visit – Foreign Body Sensation Score  (ITT 
Population– Adults and Older Children (≥ 8 years)) 
14.2.4.1.3.1 
Exploratory Endpoints: Absolute Value and Change from Baseline in 
Ocular Discomfort by Visit - Itching Score  (mITT Population– Adults 
and Older Children (≥ 8 years)) 
14.2.4.1.3.2 
Exploratory Endpoints: Absolute Value and Change from Baseline in 
Ocular Discomfort for by Visit - Itching Score  (ITT Population– Adults 
and Older Children (≥ 8 years)) 
14.2.4.1.4.1 
Exploratory Endpoints: Absolute Value and Change from Baseline in 
Ocular Discomfort by Visit – Total Score  (mITT Population– Adults and 
Older Children (≥ 8 years)) 


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Table 
Title 
14.2.4.1.4.2 
Exploratory Endpoints: Absolute Value and Change from Baseline in 
Ocular Discomfort by Visit – Total Score  (ITT Population– Adults and 
Older Children (≥ 8 years)) 
14.2.4.1.5.1 
Exploratory Endpoints: Binary Ocular Discomfort Score by Visit  (mITT 
Population - Children <8 years) 
14.2.4.1.5.2 
Exploratory Endpoints: Binary Ocular Discomfort Score by Visit  (ITT 
Population - Children <8 years) 
14.3.1.1 
Overall Treatment-emergent Adverse Events by Treatment Group (Safety 
Population) 
14.3.1.2.1 
Ocular Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group (Safety Population) 
14.3.1.2.2 
Non-Ocular Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group (Safety Population) 
14.3.1.3.1 
Frequently Occurring (≥5% in Any Treatment Group) Ocular Treatment-
emergent Adverse Events by System Organ Class, Preferred Term and 
Treatment Group (Safety Population) 
14.3.1.3.2 
Frequently Occurring (≥5% in Any Treatment Group) Non-Ocular 
Treatment-emergent Adverse Events by System Organ Class, Preferred 
Term and Treatment Group (Safety Population) 
14.3.2.1.1 
Ocular Treatment-emergent Adverse Events with an Outcome of Death by 
System Organ Class, Preferred Term  and Treatment Group  (Safety 
Population) 
14.3.2.1.2 
Non-Ocular Treatment-emergent Adverse Events with an Outcome of 
Death by System Organ Class, Preferred Term  and Treatment Group  
(Safety Population) 
14.3.2.1.3 
Ocular Treatment-emergent Serious Adverse Events by System Organ 
Class, Preferred Term and Treatment Group  (Safety Population)  
14.3.2.1.4 
Non-Ocular Treatment-emergent Serious Adverse Events by System 
Organ Class, Preferred Term and Treatment Group  (Safety Population) 
14.3.2.2.1 
Ocular Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group (Safety 
Population) 
14.3.2.2.2 
Non-Ocular Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group (Safety 
Population) 
14.3.2.3.1 
Ocular Treatment-emergent Adverse Events Leading to Discontinuation 
by System Organ Class, Preferred Term  and Treatment Group  (Safety 
Population) 
 
14.3.2.3.2 
Non-Ocular 
Treatment-emergent 
Adverse 
Events 
Leading 
to 
Discontinuation by System Organ Class, Preferred Term  and Treatment 
Group (Safety Population) 
14.3.3.1.1 
Ocular Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group (Safety Population) 


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Table 
Title 
14.3.3.1.2 
Non-Ocular Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group (Safety Population) 
14.3.4.1.1 
Ocular Local Tolerability Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and Treatment Group (Safety Population) 
14.3.4.1.1 
Ocular 
Local 
Tolerability 
Treatment-emergent 
Adverse 
Events 
Considered Related to Investigational Product by System Organ Class, 
Preferred Term and Treatment Group (Safety Population) 
14.3.4.1.1 
Ocular 
Local 
Tolerability 
Treatment-emergent 
Adverse 
Events 
Considered Not Related to Investigational Product by System Organ 
Class, Preferred Term and Treatment Group (Safety Population) 
14.3.6.1 
Best Corrected Visual Acuity (LogMar) by Visit (Safety Population) 
14.3.6.2 
Slit Lamp Biomicroscopy by Visit (Safety Population) 
14.3.6.3 
Dilated/Non-Dilated Fundus Examination by Visit (Safety Population) 
14.3.6.4 
Red Reflex Examination by Visit (Safety Population – Infants and Small 
Children) 
14.3.8.1 
Duration of Exposure to Investigational Product (Safety Population) 
14.3.8.2 
Treatment Compliance (Safety Population) 
 
Figure 
Title 
14.2.2.1.9   
Other Secondary Endpoints: Time to Clinical Resolution (days) in Study Eye – 
Kaplan-Meier Curves (mITT Population) 
 
Listing 
Title 
16.2.1.1 
Screen Failures 
16.2.1.2 
Subjects Disposition (ITT Population) 
16.2.1.3 
Early Termination by Reason (ITT Population) 
16.2.1.4 
Treatment Unmasking (ITT Population) 
16.2.2 
Protocol Deviations (ITT Population) 
16.2.3 
Study Population (ITT Population) 
16.2.4.1 
Demographics (ITT Population) 


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Listing 
Title 
16.2.4.2 
Current Conjunctivitis Event (Safety Population) 
16.2.4.3 
Ocular Medical History (Safety Population) 
16.2.4.4 
Non-Ocular Medical History (Safety Population) 
16.2.4.5.1 
Ocular Medications (Safety Population) 
16.2.4.5.2   Use of Rescue Medication  (Safety Population) 
16.2.4.6 
Non-Ocular Medications (Safety Population) 
16.2.4.7 
Ocular Procedures (Safety Population) 
16.2.4.8 
Non-Ocular Procedures (Safety Population) 
16.2.4.9 
Ocular Therapies (Safety Population) 
16.2.4.10 
Non-Ocular Therapies (Safety Population) 
16.2.5.1 
Dispensing and Return of Investigational Product (Safety Population) 
16.2.5.2 
Instillation of Investigational Product (Safety Population) 
16.2.5.3 
Investigational Product Exposure and Compliance (Safety Population) 
16.2.5.4 
Study Drug Withheld (Safety Population) 
16.2.6.1 
Conjunctival Signs Evaluation and Global Clinical Score (ITT Population) 
16.2.6.2 
Clinical Resolution Status in Study Eye (ITT Population) 
16.2.6.3 
Bacterial Eradication Status in Study Eye  (ITT Population) 
16.2.6.4 
Ocular Discomfort Evaluation (ITT Population) 
16.2.7.1 
Pre-Treatment Adverse Events (Screen Failure Subjects) 
16.2.7.2 
Pre-Treatment Adverse Events (Safety Population) 
16.2.7.3 
Treatment-Emergent Adverse Events (Safety Population) 
16.2.7.4 
Treatment-Emergent Adverse Events with an Outcome of Death (Safety Population) 
16.2.7.5 
Serious Treatment-Emergent Adverse Events (Safety Population) 
16.2.7.6 
Treatment-Emergent Adverse Events Leading to Discontinuation of Investigational 
Product (Safety Population) 


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Listing 
Title 
16.2.8.1 
Best Corrected Visual Acuity (Safety Population) 
16.2.8.2 
Slit Lamp Examination (Safety Population) 
16.2.8.3 
Fundus Examination (Safety Population) 
16.2.8.4 
Red Reflex Assessment (Safety Population) 
16.2.8.5 
Urine Pregnancy Test (Safety Population) 
16.2.8.6 
Herpes Simplex Virus Results at Visit 1  (Safety Population) 
16.2.8.7 
Chlamydia Trachomatis and Neisseria Gonorrhea Results at Visit 1  (Safety Population 
– Children <2 months)