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 Adenoviral Conjunctivitis
Phase: PHASE3
Conditions: Adenoviral Conjunctivitis
Sponsor: Shire

PROTOCOL: SHP640-302
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 Adenoviral Conjunctivitis
DRUG:
SHP640
IND:
75,723
EUDRACT NO:
2016-002440-16
SPONSOR:              Shire
                                 300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 30 June 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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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: SHP640-302..............................................................................................................1
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
STUDY SYNOPSIS ......................................................................................................................10
1.
BACKGROUND INFORMATION.......................................................................................19
1.1
Indication and Current Treatment Options...............................................................19
1.2
Product Background and Clinical Information ........................................................19
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
Secondary Objectives.............................................................................................21
2.2.3
Exploratory Objectives ..........................................................................................22
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.........................................................................................................25
4.1
Inclusion Criteria......................................................................................................25
4.2
Exclusion Criteria.....................................................................................................26
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 ...................................................................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

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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
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
Visit 2 (Day 3), Visit 3 (Day 6), and Visit 4 (Day 8) ............................................38
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
AdenoPlus Test ......................................................................................40
7.2.2
Efficacy..................................................................................................................40
7.2.2.1
Clinical Resolution.................................................................................40
7.2.2.2
Adenoviral Eradication ..........................................................................40
7.2.3
Safety .....................................................................................................................40
7.2.3.1
Best Corrected Visual Acuity (BCVA)..................................................40
7.2.3.2
Slit Lamp Biomicroscopy.......................................................................41
7.2.3.3
Intraocular Pressure................................................................................41
7.2.3.4
Non-dilated/Dilated Fundus Examination..............................................42
7.2.3.5
Adverse Event Collection.......................................................................42
7.2.3.6
Microbiology Laboratory Evaluations ...................................................42
7.2.3.7
Pregnancy Test .......................................................................................43
7.2.3.8
Health-related Quality of Life Assessments...........................................43
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................44
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events.........................................................................................................44

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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
Pregnancy...............................................................................................................46
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................46
8.2
Serious Adverse Event Procedures ..........................................................................47
8.2.1
Reference Safety Information................................................................................47
8.2.2
Reporting Procedures.............................................................................................47
8.2.3
Serious Adverse Event Definition .........................................................................48
8.2.4
Serious Adverse Event Collection Time Frame.....................................................48
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................48
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...............................................50
9.1
Data Collection.........................................................................................................50
9.2
Clinical Data Management.......................................................................................50
9.3
Data Handling Considerations..................................................................................50
9.4
Statistical Analysis Process......................................................................................50
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring 
Committee................................................................................................................51
9.6
Sample Size Calculation and Power Considerations................................................51
9.7
Study Population ......................................................................................................51
9.8
Efficacy Analyses.....................................................................................................51
9.8.1
Study Eye Designation...........................................................................................52
9.8.2
Primary Efficacy Endpoint ....................................................................................52
9.8.3
Key Secondary Efficacy Endpoints .......................................................................53
9.8.4
Secondary Efficacy Endpoints...............................................................................53
9.8.5
Exploratory Efficacy Endpoints.............................................................................54
9.9
Safety Analyses........................................................................................................54
9.10
Other Analyses .........................................................................................................55
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................56
10.1
Sponsor’s Responsibilities .......................................................................................56
10.1.1 Good Clinical Practice Compliance.......................................................................56
10.1.2 Indemnity/Liability and Insurance.........................................................................56
10.1.3 Public Posting of Study Information......................................................................56

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10.1.4 Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees........................57
10.1.5 Study Suspension, Termination, and Completion..................................................57
10.2
Investigator’s Responsibilities .................................................................................57
10.2.1 Good Clinical Practice Compliance.......................................................................57
10.2.2 Protocol Adherence and Investigator Agreement..................................................58
10.2.3 Documentation and Retention of Records.............................................................58
10.2.3.1
Case Report Forms.................................................................................58
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.3.3
Audit/Inspection.....................................................................................59
10.2.3.4
Financial Disclosure...............................................................................59
10.3
Ethical Considerations..............................................................................................59
10.3.1 Informed Consent...................................................................................................59
10.3.2 Institutional Review Board or Ethics Committee..................................................60
10.4
Privacy and Confidentiality......................................................................................61
10.5
Study Results/Publication Policy .............................................................................61
11. REFERENCES .......................................................................................................................63
12. APPENDICES ........................................................................................................................65
LIST OF TABLES
Table 1:
Schedule of Assessments...............................................................................17
Table 2:  
Common Excluded Treatments and Associated Washout Periods................31
LIST OF FIGURES
Figure 1:
SHP640-302 Study Design............................................................................23
LIST OF APPENDICES
APPENDIX 1
Protocol History.............................................................................................66
APPENDIX 2
Scales and Assessments.................................................................................73

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ABBREVIATIONS
AE
adverse event
BCVA
Best Corrected Visual Acuity
CC-IFA
cell culture-immunofluorescence assay
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
eCRF
electronic case report form
EC
ethics committee
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Conference on Harmonisation
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
PVP-I
povidone-iodine
qPCR
quantitative polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment- emergent adverse event
US
United States

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STUDY SYNOPSIS
Protocol number: SHP640-302
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 Adenoviral Conjunctivitis
Number of subjects (total and for each treatment arm):
Total subjects: Approximately 284
SHP640 treatment arm: Approximately 142
Placebo treatment arm: Approximately 142 
Investigator(s): multicenter study
Site(s) and Region(s): 
The study will be conducted in approximately 35 sites across North America, South America, Asia/Pacific, and 
Europe.
Study period (planned):
December 2016 to May 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 watery conjunctival discharge) compared with placebo in the 
treatment of subjects with adenoviral conjunctivitis in the study eye at Visit 3 (Day 6). 
Secondary:
The key secondary objective of the study is to evaluate the efficacy of SHP640 based on adenoviral eradication 
(defined as negative cell culture-immunofluorescence assay [CC-IFA]) compared with placebo in the treatment 
of subjects with adenoviral conjunctivitis in the study eye at Visit 3 (Day 6).
Secondary objectives of this study are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints:
o
Adenovirus viral titer assessed by quantitative polymerase chain reaction (qPCR) at Visit 
3 (Day 6) and 4 (Day 8)
o
Adenoviral eradication as assessed by CC-IFA at Visits 2 (Day 3), 4 (Day 8) and 5 (Day 
12)
o
Clinical resolution  of adenoviral conjunctivitis at Visits 2 (Day 3), 4 (Day 8) and 5 (Day 
12) 
o
Individual clinical signs (bulbar conjunctival injection and watery conjunctival discharge) 
at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)
o
The Global clinical score (sum of bulbar conjunctival injection and watery conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 6), 4 (Day 8) and 5 (Day 12)
o
Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 (Day 
3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)
o
Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 with neither 

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injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 
(Day 12)
o
Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 (Day 
8), and 5 (Day 12) 

To assess the status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected eye at 
baseline

To evaluate the safety and tolerability of SHP640 compared to placebo in the treatment of subjects 
with adenoviral conjunctivitis.
Rationale:
The clinical presentation of conjunctivitis is often nonspecific and differential diagnosis of different types of 
conjunctivitis can be challenging. 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. Currently there is no approved medication for the treatment of adenoviral conjunctivitis. An 
unmet need therefore exists for a safe and efficacious treatment that addresses infectious conjunctivitis 
(adenoviral and bacterial).
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 even when the cause of infection is unclear.
Investigational product, dose, and mode of administration:
The drug product is SHP640 (0.1% Dexamethasone and 0.6% PVP-I) Ophthalmic Suspension.
The placebo product is Placebo 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 (QID) for 7 days. Additional visits will occur on Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), 
and Visit 5 (Day 12). The study will last up to 13 days. 
Inclusion and exclusion criteria:
Inclusion Criteria:
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 positive AdenoPlus® test at Visit 1 in at least 1 eye.
5.
Have a clinical diagnosis of suspected adenoviral conjunctivitis in at least 1 eye (the same eye as the 
AdenoPlus positive eye) confirmed by the presence of the following minimal clinical signs and 
symptoms in that same eye:

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
Report presence of signs and/or symptoms of adenoviral conjunctivitis for ≤ 3 days prior to Visit 1

Bulbar conjunctival injection: a grade of ≥1 (mild) on a 0-4 Bulbar Conjunctival Injection Scale.

Watery conjunctival discharge: a grade of ≥1 (mild) on a 0-3 Watery 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. 
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 (e.g., uveitis, iritis, 
ulcerative keratitis, chronic blepharoconjunctivitis), other than adenoviral conjunctivitis.
9.
Have presence of corneal subepithelial infiltrates at Visit 1.
10. Have active or history of ocular herpes.
11. 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-adenoviral ocular infection (e.g., bacterial, 
fungal, acanthamoebal, other or parasitic).
12. 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.
13. 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.
14. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).

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15. 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.
16. Be a known intraocular pressure (IOP) steroid responder, have a known history of glaucoma, be a 
glaucoma suspect, or IOP > 21 mmHg at Visit 1 (Day 1).
17. Have any known clinically significant optic nerve defects. 
18. 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.
19. Presence of significant, active condition in the posterior segment which requires invasive treatment 
(eg, intravitreal treatment with VEGF inhibitors or corticosteroids) and may progress during the study 
participation period.
20. Have used any topical ocular or systemic anti-virals or antibiotics within ≤ 7 days of enrollment. 
21. Have used any topical ocular NSAIDs within ≤ 1 day of enrollment.
22. Have used any topical ophthalmic steroids in the last ≤14 days.
23. 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 peri-ocular area.
24. Have used non-corticosteroid immunosuppressive agents within ≤ 14 days of Day 1.
25. 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.
26. Have any significant ocular disease (eg, Sjogren's syndrome) or any uncontrolled systemic disease or 
debilitating disease (e.g., cardiovascular disease, hypertension, sexually transmitted diseases/infections, 
diabetes or cystic fibrosis), that may affect the study parameters, per Investigator’s discretion.
27. 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 (antihepatitis A virus immunoglobulin M), or organ or bone marrow transplantation.
28. 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 Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), and Visit 5 (Day 12). 
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 watery conjunctival 
discharge) in the study eye at Visit 3 (Day 6) between SHP640 and placebo.

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Key Secondary Efficacy Endpoints:
Adenoviral eradication status (defined as negative cell culture-immunofluorescence assay [CC-IFA]) in the 
study eye at Visit 3 (Day 6).
Secondary Efficacy Endpoints:

Absolute and change from baseline in adenovirus viral titer as assessed by qPCR at Visit 3 (Day 6) and 
4 (Day 8) in the study eye

Adenoviral eradication status as assessed by CC-IFA at Visits 2 (Day 3), 4 (Day 8) and 5 (Day 12) in 
the study eye

The clinical resolution status of adenoviral conjunctivitis at Visits 2 (Day 3), 4 (Day 8) and 5 (Day 12) 
in the study eye

The individual clinical signs score (bulbar conjunctival injection and watery conjunctival discharge) 
and change from baseline at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the study eye

The global clinical score (as defined as the sum of bulbar conjunctival injection and watery 
conjunctival discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 6), 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 6), 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 6), 4 (Day 8) and 5 (Day 12) in the  study 
eye

The status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye at Visits 2 (Day 3), 
3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected eye at baseline

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8), and 5 
(Day 12) in the study eye
Safety Endpoints:

Best Corrected Visual Acuity (BCVA)

Slit Lamp Biomicroscopy 

Intraocular Pressure

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 mITT population (unless specified otherwise) and will be presented by treatment group. Additional 
sensitivity analyses may be conducted on the ITT population. Safety analysis will be conducted on the safety 
population.
For both efficacy and safety analyses, baseline is defined as the assessments taken at Visit 1 (Day 1).
Analyses Populations:
The Safety Population will include all subjects who receive at least one dose of investigational product
The Intent to Treat (ITT) Population will include all randomized subjects. 
The Modified Intent to Treat (mITT) population consists of a subset of the ITT population who receives at 

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least one dose of investigational product and have a positive CC-IFA adenovirus test 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 watery conjunctival discharge and bulbar conjunctival redness at baseline (baseline is defined as the 
assessments taken at Visit 1 (Day 1):

For subjects with both eyes eligible and both with a positive CC-IFA result at baseline or both eyes 
eligible and both with a negative CC-IFA result at baseline, the study eye will be the eye with the 
highest global clinical score (sum of the scores for discharge and redness) 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 CC-IFA result in one eye at baseline, the baseline 
CC-IFA positive eye will be the study eye.

For subjects with only one eligible eye, the eligible eye will be the study eye irrespective of its baseline 
CC-IFA status.
Primary Efficacy Analyses:
The primary efficacy endpoint of clinical resolution will be analyzed based on the mITT population at Visit 3 
(Day 6). If subjects drop out of the study before Visit 3,then the last observation will be carried forward (LOCF) 
for the determination of clinical resolution of the 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 two-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. 
Key Secondary Efficacy Analyses:
In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary hypotheses will be 
tested sequentially using two-sided Fisher’s exact test.
The hypothesis test for the key secondary efficacy endpoint will not be performed unless hypothesis test for the 
primary efficacy endpoint is significant. 
Sensitivity analyses will also be done on key secondary efficacy endpoints using similar methods as described 
above.
Secondary Efficacy Analyses:
All secondary efficacy analyses will be performed on the mITT and presented by treatment group.  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.  Binary endpoints will be summarized by number of subjects (n), frequencies proportions 
and confidence intervals. 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. 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 SOC, 
by preferred term, and by treatment group and overall. Treatment-emergent adverse events will be further 
summarized by severity and relationship to investigational product. Adverse events related to investigational 

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product, AEs leading to withdrawal, SAEs, 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 non-ocular AE.
BCVA, Slit Lamp Biomicroscopy, intraocular pressure, non-dilated/dilated fundus exam, 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 & 
Baseline
(Day 1)
-1 day
Visit 2
(Day 3)
Visit 3
(Day 6)
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
Watery conjunctival discharge 
evaluation
X
X
X
X
X
AdenoPlus®  test
Xd
Conjunctival swab for viral culturee
Xm
Xf
Xf
Xf
Xf
Conjunctival swab for bacterial 
cultureg
X
Xf,g
Xf
Intraocular pressure
X
X
Non-dilated/ dilated fundus 
examinationh
X
X
Randomizationi
X
Dispense investigational product j
X
Instill investigational product
Xj
Xk
Xk
Collect investigational product
X
Xb
Compliance assessment
X
X
X
Xb
Drug accountability
X
Xb
Adverse events
Xl
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 & 
Baseline
(Day 1)
-1 day
Visit 2
(Day 3)
Visit 3
(Day 6)
Visit 4 
(Day 8)
Visit 5b
(Day 12)
+1 day
CC-IFA=cell culture-immunofluorescence assay; qPCR= quantitative polymerase chain reaction
a Informed consent and confirmation of inclusion/exclusion criteria can be conducted on Day -1; Inclusion/Exclusion must be re-
confirmed 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 viral testing. If the CC-IFA test is 
positive, qPCR will be performed. Adenoviral serotyping will be conducted at baseline only.
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 One swab sample from each conjunctival cul-de-sac will be collected for all bacterial testing.
h 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 Visit 1 and Visit 5 (or ET).    
i 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).
j 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.
k Investigational product instillation should only be performed in-office if it is necessary.
l Monitoring for adverse events will begin after informed consent is obtained.
m For subjects <2 months of age testing will be conducted using the same sample for chlamydia and gonorrhea  detection.

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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. Within infectious conjunctivitis, viral etiology may account for up to 80% of all cases in 
adults and bacterial conjunctivitis is the second most common cause of infectious conjunctivitis 
overall. Infectious conjunctivitis represents a serious public health issue due to a risk of highly 
infectious epidemics, lost productivity, significant patient discomfort, and in some cases 
permanent visual compromise from long-term, immune-mediated sequelae (Ford et al. 1987; 
Nauheim et al. 1990; Gordon et al. 1993; Pelletier et al. 2009; Capriotti et al. 2010).
Adenoviruses, unlike bacteria, are not part of the normal flora of the ocular surface and their 
presence is indicative of an infection (Cambon and Pollard 1959; Willamson et al. 1975; Vastine 
et al. 1977; Gigliotti et al. 1981; Kaneko et al. 2008). It is the most reported cause of viral 
conjunctivitis in up to 75% of cases (Wilkins et al. 2011). Adenoviral conjunctivitis is typically 
spread through direct contact between the eye and hands that are contaminated with the virus via 
contact with infected eye discharge, fecal matter, or respiratory discharge (CDC 2010). Given the 
highly transmittable nature of the disease, it is not surprising that it is observed to be most 
prevalent in densely populated, overcrowded areas, or in the presence of poor hygiene, or both 
(Capriotti et al. 2010).
Adenoviral conjunctivitis typically lasts 14-21 days (Wilkins et al. 2011). The onset is usually 
rapid and the infection often spreads from one eye to the other (AAO Cornea/External Disease 
PPP Panel 2013). 
Currently, there are no approved treatments for adenoviral conjunctivitis; therapeutic options are 
limited to supportive therapies and palliative measures such as cold compresses, artificial tears, 
and topical antihistamines (AAO Cornea/External Disease PPP Panel 2013). This Phase 3 study 
is being conducted to evaluate the clinical efficacy and safety of SHP640 for the treatment of 
adenoviral conjunctivitis.
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 

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dexamethasone has been shown to rapidly kill common ocular pathogens, including viruses, 
gram-positive bacteria (including MRSA), and gram-negative bacteria (Pelletier et al. 2011).
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 methicillin-
resistant Staphylococcus aureus [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). 
Currently there is no approved medication for the treatment of adenoviral conjunctivitis. An 
unmet medical need therefore exists for a safe and efficacious treatment that addresses both 
bacterial and adenoviral conjunctivitis, two 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 watery conjunctival 
discharge) compared with placebo in the treatment of subjects with adenoviral conjunctivitis in 
the study eye at Visit 3 (Day 6). 
2.2.2
Secondary Objectives
The key secondary objective of the study is to evaluate the efficacy of SHP640 based on 
adenoviral eradication (defined as negative cell culture-immunofluorescence assay [CC-IFA]) 
compared with placebo in the treatment of subjects with adenoviral conjunctivitis in the study 
eye at Visit 3 (Day 6).
Secondary objectives of this study are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints:
o
Adenovirus viral titer assessed by quantitative polymerase chain reaction (qPCR) 
at Visit 3 (Day 6) and 4 (Day 8)
o
Adenoviral eradication as assessed by CC-IFA at Visits 2 (Day 3), 4 (Day 8) and 
5 (Day 12)
o
Clinical resolution of adenoviral conjunctivitis at Visits 2 (Day 3), 4 (Day 8) and 5 
(Day 12)

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o
Individual clinical signs (bulbar conjunctival injection and watery conjunctival 
discharge) at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)
o
The global clinical score (sum of bulbar conjunctival injection and watery
conjunctival discharge) and change from baseline in the global clinical score at Visits 
2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12). 
o
Modified clinical resolution, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)
o
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 6), 4 
(Day 8) and 5 (Day 12)
o
Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 
4 (Day 8), and 5 (Day 12)

To assess the status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow 
eye at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 
infected eye at baseline

To evaluate the safety and tolerability of SHP640, compared to placebo in the treatment of 
subjects with adenoviral conjunctivitis
2.2.3
Exploratory Objectives

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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
SHP640-302 is a global, multi-center, randomized, double-masked, parallel group, placebo 
controlled study designed to demonstrate the safety and efficacy of SHP640 ophthalmic 
suspension compared to placebo in treating adenoviral conjunctivitis. 
Approximately 284 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 1:1 to receive either SHP640 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 Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), and Visit 5 (Day 12). 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:
SHP640-302 Study Design

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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 35 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 positive AdenoPlus® test at Visit 1 in at least 1 eye.
5. Have a clinical diagnosis of suspected adenoviral conjunctivitis in at least 1 eye (the 
same eye as the AdenoPlus positive 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 adenoviral conjunctivitis for ≤ 3 
days prior to Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival 
Injection Scale

Watery conjunctival discharge: a grade of ≥1 (mild) on a 0-3 Watery 
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. 

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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.
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 (e.g., 
uveitis, iritis, ulcerative keratitis, chronic blepharoconjunctivitis), other than 
adenoviral conjunctivitis.
9. Have presence of corneal subepithelial infiltrates at Visit 1.
10. Have active or history of ocular herpes.
11. 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-adenoviral 
ocular infection (e.g., bacterial, fungal, acanthamoebal, other or parasitic).
12. 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.
13. 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.
14. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
15. 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. 
16. Be a known intraocular pressure (IOP) steroid responder, have a known history of 
glaucoma, be a glaucoma suspect, or have IOP > 21 mmHg at Visit 1 (Day 1).

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17. Have any known clinically significant optic nerve defects. 
18. 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.
19. Presence of significant, active condition in the posterior segment which requires 
invasive treatment (eg, intravitreal treatment with VEGF inhibitors or corticosteroids) 
and may progress during the study participation period.
20. Have used any topical ocular or systemic anti-virals or antibiotics within ≤ 7 days of 
enrollment. 
21. Have used any topical ocular NSAIDs within ≤ 1 day of enrollment.
22. Have used any topical ophthalmic steroids in the last ≤14 days.
23. 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 peri-ocular area.
24. Have used non-corticosteroid immunosuppressive agents within ≤ 14 days of Day 1.
25. 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.
26. Have any significant ocular disease (eg, Sjogren's syndrome) or any uncontrolled 
systemic disease or debilitating disease (e.g., cardiovascular disease, hypertension, 
sexually transmitted diseases/infections, diabetes or cystic fibrosis), that may affect 
the study parameters, per Investigator’s discretion.
27. 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 (antihepatitis A virus immunoglobulin M), or 
organ or bone marrow transplantation.
28. 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 

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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

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 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 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.

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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

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 anti-virals
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
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-Iodine). 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, USP, EP, used as a preservative, and Caramel Color, NF, 
included to match the dark brown color of the PVP-I active ingredient. Additional information 
on the two 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. 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 
SHP640 or placebo based on a 1:1 ratio 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 is 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 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 (2ºC-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 2ºC-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, a mechanical recording device such as a calibrated chart recorder, or by manual 
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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.
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, when and how, must be obtained 

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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 IP, 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 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)

Ocular Discomfort Scale

Best corrected visual acuity

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
Slit lamp biomicroscopy
o
Bulbar conjunctival injection evaluation
o
Watery 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 adenoviral conjunctivitis for ≤ 3 
days prior to Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival 
Injection Scale

Watery conjunctival discharge: a grade of ≥1 (mild) on a 0-3 Watery 
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 viral culture collection (one swab per eye)

Conjunctival bacterial culture collection (one swab per eye) 

Intraocular pressure measurement

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).
7.1.2
Visit 2 (Day 3), Visit 3 (Day 6), and Visit 4 (Day 8)
Visit 2 (Day 3), Visit 3 (Day 6), and Visit 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.

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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 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.  
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. 

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
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 as outlined in Table 1. A positive result in at 
least one eye 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 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 adenoviral 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 which 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
Adenoviral Eradication
Adenoviral eradication for an eye is defined as negative CC-IFA in that eye.  CC-IFA for each 
eye will be conducted using conjunctival swab samples collected at each visit. See the 
Laboratory Manual for further details.
7.2.3
Safety
Safety assessments will be performed in both eyes.
7.2.3.1
Best Corrected Visual Acuity (BCVA)
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 Operations Manual. Changes in 
VA will be assessed for clinical significance. Clinically significant changes should be recorded 
in the source and on the 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 Operations Manual). The policy statement recommends formal 

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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.
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 hand held 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 electronic CRF 
(eCRF) (in Medical History at Screening; any changes from the screening visit may be recorded 
as adverse events 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
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 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 Operations Manual). The examination of lens in these subjects 
should be conducted at Visit 1 and Visit 5 (or ET visit) and graded based on the external 
examination and red reflex exam (Section 7.2.3.4). 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
Intraocular Pressure
At Visit 1 and Visit 5 (or Early Termination visit), IOP will be assessed in both eyes using either 
Goldmann tonometer or a Tono-pen®. The same method of measurement must be used for each 
patient throughout the entire time of participation in the study. For both methods (Goldmann and 
Tono-Pen®), sterile disposable single-use tips must be used each time to prevent 
cross-contamination. Other measures as appropriate should be taken to prevent 

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cross-contamination. For children <12 years of age, measurement of IOP will be performed at 
the discretion of the Investigator.
7.2.3.4
Non-dilated/Dilated Fundus Examination
Fundus examination must be conducted after BCVA, Slit Lamp Biomicroscopy and conjunctival 
swab for adenoviral and 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, dilated fundus exam should be 
conducted. The test should be conducted the same way (either dilated or non-dilated) at both 
Visit 1 and Visit 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 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 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.
7.2.3.5
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 TEAE.
Adverse events may also be determined by the investigator during study examinations as 
mentioned in previous sections.
7.2.3.6
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 FDA/ICH guidelines, based on 
the method's intended use. The lab will only receive sample ID numbers and collection dates, the 

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lab results will then be transferred to the central lab for data analysis. The lab will not receive 
any information on subject treatment assignment.
The following laboratory assessments will be performed: 

Cell Culture Assay (CC-IFA): This test will be performed on samples collected at all 
visits to determine the presence of adenovirus. 

quantitative Polymerase Chain Reaction (qPCR): This test will be performed on all CC-
IFA positive samples at all visits to determine viral count.

Adenoviral serotyping: This test will be done at baseline only to determine what 
serotypes of adenovirus are present.
One swab sample from each eye will be taken from inferior conjunctival cul-de-sac at all study 
visits for adenoviral testing. For neonates and infants <2 months of age, PCR testing for presence 
of chlamydia and gonorrhea at baseline will also be conducted using the baseline visit sample.
7.2.3.7
Pregnancy Test 
A urine pregnancy test is performed on all females of childbearing potential at Visit 1 and Visit 
5, or if pregnancy is suspected.  Urine pregnancy test kits will be provided by the sponsor and 
read on site by qualified site personnel.
7.2.3.8
Health-related Quality of Life Assessments
Ocular discomfort associated with conjunctivitis symptoms will be assessed through the Ocular 
Discomfort Scale. The Ocular Discomfort Scale is composed of three 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 less than 8 years of age (binary ocular discomfort). Please see the 
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, 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
A serious adverse event (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 inpatient 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 inpatient 
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 IRBs/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 the 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 investigators’ 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.
The SAP 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 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
There is no planned interim analysis, adaptive design, or data monitoring committee (DMC) in 
this study.
9.6
Sample Size Calculation and Power Considerations
Subjects will be randomized 1:1 to receive either SHP640 (PVP-Iodine 0.6% /dexamethasone 
0.1%) ophthalmic suspension or placebo within each stratum. 
A sample size of 184 subjects (92 subjects in each treatment arm) will ensure 90% power to 
compare the SHP640 and Placebo treatment groups assuming 31% and 11% subjects with 
clinical resolution respectively using Fisher’s Exact test at two-sided 5% level of significance.
All efficacy analyses will be based on the mITT population with post-baseline LOCF for the 
subjects with missing clinical resolution status at Visit 3 (Day 6).  To ensure approximately 184
subjects in the mITT population, approximately 284 subjects will be randomized in this study.
9.7
Study Population
The Safety Population will include all subjects who receive at least one dose of investigational 
product.
The Intent to Treat (ITT) Population will include all randomized subjects. 
The Modified Intent to Treat (mITT) population consists of a subset of the ITT population 
who receive at least one dose of investigational product and have a positive CC-IFA adenovirus 
test 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 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 watery conjunctival discharge and bulbar conjunctival redness at 
baseline (baseline is defined as the assessments taken at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive CC-IFA result at baseline or 
both eyes eligible and both with a negative CC-IFA result at baseline, the study eye will 
be the eye with the highest global clinical score (sum of the scores for discharge and 
redness) 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 CC-IFA result in one eye at baseline, 
the baseline CC-IFA positive eye will be the study eye.

For subjects with only one eligible eye, the eligible eye will be the study eye irrespective 
of its baseline CC-IFA status.
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 watery conjunctival discharge) in the study eye at Visit 3 
(Day 6) between SHP640 and placebo.
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 6) 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 6) using Fisher’s 
Exact test at two sided 0.05 significance level. 
If subjects have missing clinical resolution status at Visit 3 (Day 6), then the last post-baseline 
observation will be carried forward (LOCF) 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 two-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 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 (birth to<6 years and 6 to <18 years) in mITT. A 

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detailed plan for primary analysis including additional sensitivity analyses will be described in 
the Statistical Analysis Plan (SAP).
9.8.3
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoint of this study is adenoviral eradication status (defined as 
negative cell culture-immunofluorescence assay [CC-IFA]) in the study eye at Visit 3 (Day 6).
In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary 
hypotheses will be tested sequentially using two-sided Fisher’s exact test.
The hypothesis test for the key secondary efficacy endpoint will not be performed unless the 
hypothesis test for the primary efficacy endpoint is significant.
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 (birth to <6 years and 6 to <18 years) in mITT. Details on the 
analyses will be described in the Statistical Analysis Plan (SAP).
9.8.4
Secondary Efficacy Endpoints
All secondary efficacy analyses will be performed on the mITT 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.  Binary endpoints 
will be summarized by number of subjects (n), frequencies, proportions and confidence intervals.
Time to event endpoint will be summarized by Kaplan-Meier survival estimates.
Secondary efficacy endpoints are defined as follows:

Absolute and change from baseline in adenovirus viral titer as assessed by qPCR at Visits 3 
(Day 6) and 4 (Day 8) in the study eye

Adenoviral eradication status as assessed by CC-IFA at Visits 2 (Day 3), 4 (Day 8) and 5 
(Day 12) in the study eye

Clinical resolution status of adenoviral conjunctivitis at Visits 2 (Day 3), 4 (Day 8) and 5 
(Day 12) in the study eye 

Individual clinical signs score (bulbar conjunctival injection and watery conjunctival 
discharge)  and change from baseline at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)
in the study eye 

The global clinical score (defined as the sum of bulbar conjunctival injection and watery 
conjunctival discharge) and change from baseline in the global clinical score at Visits 2 
(Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the study eye 

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
Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 
(Day 3), 3 (Day 6), 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 6), 4 (Day 
8) and 5 (Day 12) in the study eye 

The status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected 
eye at baseline

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 (Day 
8), and 5 (Day 12) in the study eye
9.8.5
Exploratory Efficacy Endpoints
9.9
Safety Analyses
Safety data will be presented for the Safety Population by treatment group and overall.
Safety data collected at baseline (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 
treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated 
overall, by SOC, by preferred term, and by treatment group and overall. 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 
non-ocular AE.

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The following safety endpoints will be descriptively summarized by treatment group and overall 
at each applicable visit:

Best Corrected Visual Acuity (BCVA)

Slit Lamp Biomicroscopy
o
Lids 
o
Conjunctiva 
o
Cornea 
o
Anterior Chamber
o
Iris
o
Lens 

Intraocular Pressure

Non-dilated/ Dilated Fundus Examination
o
Vitreous 
o
Optic Nerve 
o
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, 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 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 good clinical practice (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 which 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, the 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 documented by resigning 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, ocular discomfort scale, and documented results of AdenoPlus test.

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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, 
EMA, UK 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; 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 

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information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the 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 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 which 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 

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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
AAO Cornea/External Disease PPP Panel 2013. American Academy of Ophthalmology (AAO), 
2013 - Cornea/External Disease Preferred Practice Pattern Guidelines. Conjunctivitis. San 
Francisco, CA.
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® antiseptic solution (povidone-iodine) 2004. Mundipharma AG, Basel, Switzerland 
[cited 2016 Jan 26]. Available from http://home.intekom.com/pharm/adcock/betadn-s.html.
Cambon, E. N. & Pollard, M. 1959. Viral studies of the normal eye. Arch Ophthalmol, 62, 562-5.
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.
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.
Gigliotti, F., Williams, W. T., Hayden, F. G., Hendley, J. O., Benjamin, J., Dickens, M., 
Gleason, C., Perriello, V. A. & Wood, J. 1981. Etiology of acute conjunctivitis in children. J 
Pediatr, 98, 531-6.
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.
Kaneko, H., Maruko, I., Iida, T., Ohguchi, T., Aoki, K., Ohno, S. & Suzutani, T. 2008. The 
possibility of human adenovirus detection from the conjunctiva in asymptomatic cases during 
nosocomial infection. Cornea, 27, 527-30.
MAXIDEX® (0.1% dexamethasone ophthalmic suspension) [package insert] 2007. Alcon 
Laboratories, Inc, Fort Worth (TX) [cited 2016 Jan 27]. Available from 
http://ecatalog.alcon.com/PI/Maxidex_us_en.pdf. 

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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.
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.
Pocock, S. J. & Simon, R. 1975. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 31, 103-15.
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.
Vastine, D. W., Schwartz, H. S., Yamashiroya, H. M., Smith, R. F. & Guth, S. B. 1977. 
Cytologic diagnosis of adenoviral epidemic keratoconjunctivitis by direct immunofluorescence. 
Invest Ophthalmol Vis Sci, 16, 195-200.
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.
Wilkins, M. R., Khan, S., Bunce, C., Khawaja, A., Siriwardena, D. & Larkin, D. F. 2011. A 
randomised placebo-controlled trial of topical steroid in presumed viral conjunctivitis. Br J 
Ophthalmol, 95, 1299-303.
Willamson, J., Doig, W. M., Forrester, J. V., Carson, W. & Whaley, K. 1975. Studies of the viral 
flora in keratoconjunctivitis sicca. Br J Ophthalmol, 59, 45-6.

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12.
APPENDICES

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Section 6.2.2
The number of planned study sites was updated for accuracy.
Synopsis
Section 3.3
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):

Previous Exclusion Criteria 6 was removed as there is no longer 
a prespecified household cap.

chronic blepharoconjunctivitis was added to Exclusion Criteria 8

Exclusion Criteria 12 and 13 were modified to reflect the 
removal of the lower age limit.

Exclusion Criteria 11, 14, and 15 were added.

Previous Exclusion Criteria 16 was removed (History of corneal 
transplant in either eye).

Corneal epithelial defect was added to Exclusion Criteria 18.

Antibiotics were added to Exclusion Criteria 20.

Exclusion Criteria 22 was modified as follows: Have used any 
topical ophthalmic steroids in the last ≤14 30 days.

Restriction of inhaled systemic corticosteroid agents was 
removed from Exclusion Criteria 23.

Exclusion Criteria 24 was updated to clarify that non-
corticosteroid immunosuppressive agents within ≤14 days of Day 
1

Exclusion Criteria 25 was modified to note that use of hot or cold 
compresses is also not permitted during the study.

Previous Exclusion Criteria 25 (Have any autoimmune disease.) 
was removed.
Synopsis
Section 4.2
Contraception text modified. Intrauterine hormone-releasing systems plus 
condoms was added as an acceptable form of contraception and the note 
related to subjects that become sexually active during the study was 
removed due to the short study duration.
Section 4.3.1

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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, if in 
the judgment of the investigator, treatment with an alternate therapy is in 
the best interest of subject for safety reasons 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 
necessary.
Section 4.4
Table 2 “Common Excluded Treatments and Associated Washout 
Periods” was updated.
Section 5.2.2
Emergency unmasking added to list of IRT vendor responsibilities.
Section 6.2.1
Pocock and Simon 1975 reference added for dynamic balanced 
randomization. 
Noted that randomization will be done centrally.
Section 6.2.2
Storage requirement language moved to correct location from Section 
6.2.3 to Section 6.3.3.
Section 6.2.3
Section 6.3.3
Treatment unmasking language was updated.
Section 6.2.4
Specific treatment compliance range was removed.
Section 6.5
Section 7.1.2
Order of assessments and the details of study procedures in Visit 1 were
updated for accuracy.
Section 7.1.1
Noted that subjects should be reminded to not dose the morning of Visits 
2, 3 and 4.
Section 7.1.2
Clarified that demographic information will be collected at Visit 1. Date 
of Birth (where permitted), Age, Sex, Race, and Ethnicity will be recorded
Section 7.2.1.1
Updated to note that the site must record all clinically or medically 
relevant information regardless of how much time has elapsed since the 
date of any diagnosis. Previous protocol assigned this responsibility 
specifically to the investigator.
Clarified that Medical history will be classified as ocular (specified as left 
eye, right eye or both eyes).
Section 7.2.1.2
It was noted that a positive AdenoPlus result in at least one eye is required 
for enrollment in this study.
Section 7.2.1.3
Definition of adenoviral eradication updated to be non-specific to the 
study eye:
Adenoviral eradication for an eye is defined as negative CC-IFA in that
the study eye. CC-IFA for each eye will be conducted using conjunctival 
swab samples collected at each visit. from the study eyes. 
This change is also reflected in wording of the second key secondary 
objective.
Section 7.2.2.2
Section 2.2.2
Synopsis
Best Corrected Visual Acuity subsection was moved to indicate order of 
Section 7.2.3.1

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procedures.
Clarified that the following will be examined at each visit via slit lamp 
biomicroscopy: 

Lids 

Conjunctiva 

Cornea

Anterior Chamber

Iris

Lens
Added additional details for process for infants and children. 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 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 Operations Manual). The examination of 
lens in these subjects should be conducted at Visit 1 and Visit 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.
Synopsis
Section 7.2.3.2
Section 7.2.3.3 was added to describe intraocular pressure assessments at 
Visit 1 and Visit 5.
Section 7.2.3.3
Updated to indicate the fundus examination must be conducted after 
BCVA, Slit Lamp Biomicroscopy and conjunctival swab for adenoviral 
and bacterial culture has been collected. Clarified  that a non-dilated or 
dilated fundus examination may conducted, and that the following will be 
evaluated: Vitreous, Optic Nerve, and Macula.
Clarified that a dilated fundus examination should be conducted if a non-
dilated fundus examination is not feasible (for instance, in young children 
and infants).
Updated to indicate that for infants and small children in whom a fundus 
examination cannot be done, a red reflex exam will be conducted in 
accordance with 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 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.
Synopsis
Section 7.2.3.4 (formerly 7.2.3.3)

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Update to indicate that two swab samples  (one for adenoviral and one for 
bacterial) from each eye will be taken from inferior conjunctival cul-de-
sac at all study visits.  Updated to indicate that for neonates and infants <2 
months of age, PCR testing for presence of chlamydia and gonorrhea at 
baseline will also be conducted using the baseline visit sample.
Section title and content fore Section 7.2.3.5 was modified as the lab 
assessments for this study are not standard clinical laboratory assessments.
Section 7.2.3.6 (formerly 7.2.3.5)
Description of the ODS was updated to note that there are 3 components 
to the assessment: pain, itching, and foreign body sensation. It was also 
noted that a separate scale will be administered for children less than 8 
years of age.
Section 7.2.3.8 (formerly 7.2.3.7)
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
Clarified that All efficacy analyses will be based on the mITT population 
with post-baseline LOCF for the subjects with missing clinical resolution 
status at who drop out before Visit 3 (Day 6).  
Section 9.6
It was noted that exploratory efficacy endpoints will be performed on the 
mITT population and will be presented by treatment group.
It was clarified that for both efficacy and safety analyses, baseline is 
defined as the assessments taken at Visit 1 (Day 1).
Section 9.8
Description of the analysis of the primary endpoint was updated as 
follows:
The primary efficacy endpoint of is clinical resolution status (defined as 
absence [ie a score of 0] of bulbar conjunctival injection and watery 
conjunctival discharge) in the study eye at Visit 3 (Day 6) between 
SHP640 and placebo.
All efficacy analyses will be analyzed based 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 6) 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 6) using Fisher’s Exact test at 
two sided 0.05 significance level. 
If subjects have missing clinical resolution status at drop out of the study 
before Visit 3 (Day 6), then the last post-baseline observation will be 
carried forward (LOCF) 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 
Synopsis
Section 9.6
Section 9.8.2

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difference in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 
two-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 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 analysis plan for primary 
analysis including additional methods to be usedsensitivity analyses will 
be described in the Statistical Analysis Plan (SAP).
For key secondary endpoints it was clarified that: 
All efficacy analyses will be performed on the mITT 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 using two-sided Fisher’s exact test according to the following 
sequence: 
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 mITT. 
Details on the analyses will be described in the Statistical Analysis Plan 
(SAP).
Synopsis
Section 9.8.3
Noted that Binary endpoints will be summarized by number of subjects 
(n), frequencies, proportions and confidence intervals. It was noted that 
Time to event endpoint will be summarized by Kaplan-Meier survival 
estimates. Time to clinical resolution was added.
Section 9.8.4
Section 9.8.5

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Noted that safety analyses will be presented by treatment group and 
overall.
Noted that AE assessments will include local tolerability.
Specific components of Slit Lamb Biomicroscopy and Non-dilated/dilated 
fundus examination were added as follows:

Slit Lamp Biomicroscopy
o
Lids 
o
Conjunctiva 
o
Cornea 
o
Anterior Chamber 
o
Iris
o
Lens 

Non-dilated/ Dilated Fundus Examination
o
Vitreous 
o
Optic Nerve 
o
Macula
Synopsis
Section 9.9
It was noted that in case of substantial amendment, approval from the 
Competent Regulatory Authority will be sought before implementation.  
Section 10
Clarified that the investigator, study sponsor and any third party to whom 
aspects of the study management or monitoring have been delegated must 
undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC and its updates, as well as all applicable 
national and local laws and regulations.
Section 10.1.1
Section 10.2.1
Clarified that the documented results of the AdenoPlus test be reviewed, 
not the test itself.
Section 10.2.3.2
Noted that the Operations  Manual will be provided upon request
Appendix 2

Shire
CONFIDENTIAL
Page 73
SHP640-302 Protocol Amendment 1
28 Nov 2016
SHP640 (FST-100)
APPENDIX 2
SCALES AND ASSESSMENTS
All scales assessments referenced in the protocol, including procedural instructions for the 
Investigator, are in the Operations Manual and the Laboratory Manual (provided upon request).