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 PVP-Iodine and Placebo in the Treatment of Adenoviral Conjunctivitis
Phase: PHASE3
Conditions: Adenoviral Conjunctivitis
Sponsor: Shire

PROTOCOL SHP640-301
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 
PVP-Iodine and Placebo in the Treatment of Adenoviral Conjunctivitis
DRUG:
SHP640
IND:
75,723
EUDRACT NO:
2016-002439-14
SPONSOR:
Shire
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 30 June 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 SHP640-301...............................................................................................................1
PROTOCOL SIGNATURE PAGE .................................................................................................1
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
LIST OF TABLES...........................................................................................................................8
LIST OF FIGURES .........................................................................................................................8
LIST OF APPENDICES..................................................................................................................8
ABBREVIATIONS .........................................................................................................................9
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 ..............................................................................20
2.1
Rationale for the Study.............................................................................................20
2.2
Study Objectives ......................................................................................................20
2.2.1
Primary Objectives.................................................................................................20
2.2.2
Secondary Objectives.............................................................................................20
2.2.3
Exploratory Objectives ..........................................................................................21
3.
STUDY DESIGN ...................................................................................................................22
3.1
Study Design and Flow Chart ..................................................................................22
3.2
Duration and Study Completion Definition .............................................................23
3.3
Sites and Regions .....................................................................................................23
4.
STUDY POPULATION.........................................................................................................24
4.1
Inclusion Criteria......................................................................................................24
4.2
Exclusion Criteria.....................................................................................................24
4.3
Reproductive Potential .............................................................................................26
4.3.1
Female Contraception............................................................................................26
4.4
Discontinuation of Subjects .....................................................................................27
4.4.1
Reasons for Discontinuation..................................................................................27
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................28
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................29
5.1
Prior Treatment ........................................................................................................29
5.2
Concomitant Treatment............................................................................................29
5.2.1
Permitted Treatment...............................................................................................29
5.2.2
Prohibited Treatment .............................................................................................29
6.
INVESTIGATIONAL PRODUCT ........................................................................................31
6.1
Identity of Investigational Product...........................................................................31

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6.1.1
Masking the Treatment Assignment ......................................................................31
6.1.2
Commercially Obtained Investigational Product...................................................31
6.2
Administration of Investigational Product(s)...........................................................31
6.2.1
Interactive Response Technology for Investigational Product Management ........31
6.2.2
Allocation of Subjects to Treatment ......................................................................31
6.2.3
Dosing....................................................................................................................32
6.2.4
Unmasking the Treatment Assignment..................................................................32
6.3
Labeling, Packaging, Storage, and Handling ...........................................................33
6.3.1
Labeling .................................................................................................................33
6.3.2
Packaging...............................................................................................................33
6.3.3
Storage ...................................................................................................................33
6.3.4
Special Handling....................................................................................................34
6.4
Drug Accountability.................................................................................................34
6.5
Subject Compliance..................................................................................................35
7.
STUDY PROCEDURES........................................................................................................36
7.1
Study Schedule.........................................................................................................36
7.1.1
Visit 1 (Day 1) .......................................................................................................36
7.1.2
Visit 2 (Day 3), Visit 3 (Day 6), and Visit 4 (Day 8) ............................................37
7.1.3
Visit 5 (End of Study or Early Termination) .........................................................38
7.1.4
Additional Care of Subjects after the Study ..........................................................38
7.2
Study Evaluations and Procedures ...........................................................................38
7.2.1
Demographic and Other Baseline Characteristics .................................................38
7.2.1.1
Demographics.........................................................................................38
7.2.1.2
Medication and Medical History............................................................38
7.2.1.3
RPS AdenoPlus Test ..............................................................................39
7.2.2
Efficacy..................................................................................................................39
7.2.2.1
Clinical Resolution.................................................................................39
7.2.2.2
Adenoviral Eradication ..........................................................................39
7.2.3
Safety .....................................................................................................................39
7.2.3.1
Slit Lamp Biomicroscopy.......................................................................39
7.2.3.2
Non-dilated Fundus Examination...........................................................40
7.2.3.3
Best Corrected Visual Acuity (BCVA)..................................................40
7.2.3.4
Adverse Event Collection.......................................................................41
7.2.3.5
Clinical Laboratory Evaluations.............................................................41
7.2.3.6
Pregnancy Test .......................................................................................42
7.2.3.7
Health-related Quality of Life Assessments...........................................42
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................43

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8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................43
8.1.1
Severity Categorization..........................................................................................43
8.1.2
Relationship Categorization...................................................................................44
8.1.3
Outcome Categorization ........................................................................................44
8.1.4
Symptoms of the Disease Under Study .................................................................44
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................45
8.1.6
Pregnancy...............................................................................................................45
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................46
8.2
Serious Adverse Event Procedures ..........................................................................46
8.2.1
Reference Safety Information................................................................................46
8.2.2
Reporting Procedures.............................................................................................47
8.2.3
Serious Adverse Event Definition .........................................................................47
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........................................................................................................48
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................48
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................49
9.1
Data Collection.........................................................................................................49
9.2
Clinical Data Management.......................................................................................49
9.3
Data Handling Considerations..................................................................................49
9.4
Statistical Analysis Process......................................................................................49
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......50
9.6
Sample Size Calculation and Power Considerations................................................50
9.7
Study Population ......................................................................................................50
9.8
Efficacy Analyses.....................................................................................................51
9.8.1
Study Eye Designation...........................................................................................51
9.8.2
Primary Efficacy Endpoint ....................................................................................51
9.8.3
Key Secondary Efficacy Endpoints .......................................................................52
9.8.4
Secondary Efficacy Endpoints...............................................................................53
9.8.5
Exploratory Efficacy Endpoints.............................................................................53
9.9
Safety Analyses........................................................................................................54
9.10
Other Analyses .........................................................................................................54
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................55
10.1
Sponsor’s Responsibilities .......................................................................................55
10.1.1 Good Clinical Practice Compliance.......................................................................55
10.1.2 Indemnity/Liability and Insurance.........................................................................55
10.1.3 Public Posting of Study Information......................................................................55

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10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................55
10.1.5 Study Suspension, Termination, and Completion..................................................56
10.2
Investigator’s Responsibilities .................................................................................56
10.2.1 Good Clinical Practice Compliance.......................................................................56
10.2.2 Protocol Adherence and Investigator Agreement..................................................56
10.2.3 Documentation and Retention of Records.............................................................57
10.2.3.1
Case Report Forms.................................................................................57
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................57
10.2.3.3
Audit/Inspection.....................................................................................58
10.2.3.4
Financial Disclosure...............................................................................58
10.3
Ethical Considerations..............................................................................................58
10.3.1 Informed Consent...................................................................................................58
10.3.2 Institutional Review Board or Ethics Committee..................................................59
10.4
Privacy and Confidentiality......................................................................................59
10.5
Study Results/Publication Policy .............................................................................60
11. REFERENCES .......................................................................................................................62
12. APPENDICES ........................................................................................................................64
LIST OF TABLES
Table 1:
Schedule of Assessments...............................................................................17
Table 2:  
Common Excluded Treatments and Associated Washout Periods................30
LIST OF FIGURES
Figure 1:
SHP640-301 Study Design............................................................................22
LIST OF APPENDICES
Appendix 1
Protocol History .....................................................................................65
Appendix 2
Scales and Assessments .........................................................................66

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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
MRSA
methicillin-resistant Staphylococcus aureus
PVP-I
povidone-iodine
qPCR
quantitative polymerase chain reaction
RPS
Rapid Pathogen Screening, Inc.
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment- emergent adverse event
US
United States

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STUDY SYNOPSIS
Protocol number: SHP640-301
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 PVP-Iodine and Placebo in the Treatment of Adenoviral Conjunctivitis
Number of subjects (total and for each treatment arm):
Total subjects: Approximately 930
SHP640 treatment arm: Approximately 372
Povidone-iodine (PVP-I) treatment arm: Approximately 372
Placebo treatment arm: Approximately 186
Investigator(s): multicenter study
Site(s) and Region(s): 
The study will be conducted in approximately 80 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:
Key secondary objectives of this study are as follows:

To evaluate the efficacy of SHP640 based on clinical resolution compared with PVP-I in the 
treatment of subjects with adenoviral conjunctivitis in the study eye at Visit 3 (Day 6). 

To evaluate the efficacy of PVP-I based on adenoviral eradication (defined as negative cell 
culture-immunofluorescence assay [CC-IFA] in the study eye) compared with placebo in the 
treatment of subjects with adenoviral conjunctivitis in the study eye at Visit 2 (Day 3).

To evaluate the efficacy of SHP640 based on adenoviral eradication compared with placebo in the 
treatment of subjects with adenoviral conjunctivitis in the study eye at Visit 3 (Day 6).

To evaluate the efficacy of SHP640 based on adenoviral eradication compared with PVP-I in the 
treatment of subjects with adenoviral conjunctivitis in the study eye at Visit 3 (Day 6). 

To evaluate the efficacy of PVP-I based on clinical resolution 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 4 (Day 8) and 5 (Day 12)
o
Clinical resolution of adenoviral conjunctivitis at Visits 2 (Day 3), 4 (Day 8) and 5 (Day 

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12) 
o
Individual clinical resolution endpoints (bulbar conjunctival injection and watery 
conjunctival discharge) at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)
o
Global clinical score (sum of bulbar conjunctival injection and watery conjunctival 
discharge) 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)

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 PVP-I and 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 comparator is 0.6% PVP-I Ophthalmic Solution.
The placebo product is Placebo Ophthalmic Solution.
Subjects will instill 1 drop of study medication 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 study medication 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 Day 3 (Visit 2), Day 6 (Visit 3), Day 8 (Visit 4), and Day 
12 (Visit 5). 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.
Be ≥1 month of age at Visit 1. 

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4.
Have a positive RPS 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 
RPS 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 (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. Every attempt should be made to obtain a BCVA measurement in children and, if 
it is unobtainable, the decision as to whether the criterion is met will be at the investigator's discretion. 
8.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of non-childbearing potential. 
Exclusion Criteria:
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.
Subjects from a household that has met the prespecified household enrollment cap
7.
Have a history of ocular surgical intervention within ≤ 6 months prior to Visit 1 or planned for the 
period of the study.
8.
Have a preplanned overnight hospitalization during the period of the study.
9.
Have presence of any intraocular, corneal, or conjunctival ocular inflammation (e.g., uveitis, iritis, 
ulcerative keratitis), other than adenoviral conjunctivitis.
10. Have presence of corneal subepithelial infiltrates at Visit 1.
11. Have active or history of ocular herpes.
12. Have clinical signs or presence of ocular allergy or an ocular infection (e.g., bacterial, acanthamoeba, 
fungal or other ocular viral infection) currently or within ≤ 30 days of Visit 1 other than adenoviral 
conjunctivitis 
13. Be a known intraocular pressure (IOP) steroid responder, have a known history of glaucoma, be a 
glaucoma suspect, or have a known history of an elevated IOP > 21 mmHg.
14. Have any known clinically significant optic nerve defects. 
15. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to previous 

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corneal trauma or dry eye syndrome; presence of any significant corneal opacity at Visit 1.
16. History of corneal transplant in either eye.
17. 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. 
18. Have used any topical ocular or systemic anti-virals within ≤ 7 days of enrollment. 
19. Have used any topical ocular NSAIDs within ≤ 1 day of enrollment.
20. Have used any topical ophthalmic steroids in the last ≤ 30 days.
21. Have used any inhaled or 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.
22. Have used immunosuppressive agents within ≤ 14 days of Day 1.
23. Have used any topical ophthalmic products, including tear substitutes and, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all topical 
ophthalmic products for the duration of the study.
24. Have any significant ocular disease (eg, Sjogren's syndrome) or any uncontrolled systemic disease or 
debilitating disease (e.g., cardiovascular disease, hypertension, sexually transmitted diseases/infections, 
diabetes or cystic fibrosis), that may affect the study parameters, per Investigator’s discretion.
25. Have any autoimmune disease.
26. Any known history of immunodeficiency disorder or 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.
27. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device

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 Day 3 (Visit 2), Day 6 (Visit 3), Day 8 (Visit 4), and Day 12 (Visit 5). 
All follow-up procedures will be conducted at Visit 5 (Day 12).
Endpoints and statistical analysis:
Primary Efficacy Endpoint:
Clinical resolution (defined as absence of bulbar conjunctival injection and watery conjunctival discharge) in the 
study eye at Visit 3 (Day 6) between SHP640 and placebo.
Key Secondary Efficacy Endpoints:
Clinical resolution at Visit 3 (Day 6) and adenoviral eradication status (defined as negative cell culture-
immunofluorescence assay [CC-IFA]) in the study eye at Visits 2 (Day 3) and 3 (Day 6).
Five hypotheses tests will be performed on the key secondary efficacy endpoints at Visit 3 (Day 6) unless 
specified otherwise in following order:
1.
Comparison of proportion of subjects achieving clinical resolution between SHP640 and PVP-I.

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2.
Comparison of proportion of subjects achieving adenoviral eradication between PVP-I and Placebo at 
Visit 2 (Day 3).
3.
Comparison of proportion of subjects achieving adenoviral eradication between SHP640 and Placebo.
4.
Comparison of proportion of subjects achieving adenoviral eradication between SHP640 and PVP-I.
5.
Comparison of proportion of subjects achieving clinical resolution between PVP-I and Placebo.
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 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 resolution endpoints scores (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, 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, 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
Safety Endpoints:

Adverse Events (AEs)

Slit Lamp Biomicroscopy

Non-dilated Fundus Examination

Best Corrected Visual Acuity (BCVA)

Urine Pregnancy Testing (for females of childbearing potential)
Statistical Methods:
The analyses on primary, key secondary, secondary efficacy endpoints will be performed on the mITT 
population. 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 receive at 
least one dose of study medication and have a positive CC-IFA adenovirus test at baseline in the study eye.
Designation of Study Eye:

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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 according to the following sequence: 
Sensitivity analyses will also be done on key secondary efficacy endpoints using similar methods as described 
above.
Secondary Efficacy Analyses:
No hypothesis testing is planned for the secondary efficacy endpoints.  All secondary efficacy endpoints will be 
summarized by treatment groups using descriptive statistics at each assessment visit.  Continuous endpoints will 
be summarized by sample size, mean, median, standard deviation, minimum, maximum and confidence 
intervals.  Binary endpoints will be summarized by sample size, proportions and confidence intervals.
Safety Analyses:
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The number of events, 
incidence, and percentage of TEAEs will be calculated overall, by SOC, by preferred term, and by treatment 

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group. Treatment-emergent adverse events will be further summarized by severity and relationship to 
investigational product. Adverse events related to investigational product, AEs leading to withdrawal, SAEs, 
and deaths will be similarly summarized and listed. Any AE that occurs after the first dose of study medication 
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.
Slit Lamp Biomicroscopy, non-dilated fundus exam, BCVA, urine pregnancy test (for females of childbearing 
potential) will be descriptively summarized by treatment group at each measured time point.

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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/assent a
X
Inclusion/exclusion criteria a
X
Medical history 
X
Demographics
X
Concomitant medications
X
X
X
X
X
Urine pregnancy test
Xc
Xc
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
RPS AdenoPlus® test
X
Non-dilated fundus examination
X
X
Ocular Discomfort Scale
X
X
X
X
X
Conjunctival swab for viral cultured
X
Xe
Xe
Xe
Xe
Conjunctival swab for bacterial culturef
X
X
X
Randomizationg
X
Dispense study medication h
X
Instill medication
Xh
Xi
Xi
Collect study medication
X
Xb
Compliance assessment
X
X
X
Xb
Drug accountability
X
Xb
Adverse events
X,j
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; RPS=Rapid Pathogen Screening, Inc.
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 One swab sample from each conjunctival cul-de-sac 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.
e Conjunctival viral culture MUST be taken at least 12 hours after the last dose of study medication at Visits 2, 3, 4 and ET, if applicable.
f One swab sample from each conjunctival cul-de-sac will be collected for all bacterial testing.
g In order to ensure QID dosing on Day 1 (with a minimum of 2 hours between doses); all assessments, randomization, and medication instillation on Day 1 must 
take place with sufficient time to allow all 4 Day 1 doses.
h The study drug bottle should be shaken well prior to use at each dosing. The first dose will be administered by site staff on Day 1, and thereafter subjects will 
administer 1 drop in each eye 4 times a day for 7 days.
i Medication instillation should only be performed in-office if it is necessary to keep patient on dosing schedule.
j Monitoring for adverse events will begin after informed consent is obtained.

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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, combining povidone-iodine (PVP-I) (0.6%) 
with dexamethasone (0.1%), is currently under development for the treatment of infectious 
conjunctivitis (adenoviral and bacterial). In addition to alleviating signs and symptoms, SHP640 
may decrease the infectivity of adenovirus and bacteria in infected individuals, have a substantial 
impact on the spread of disease, and lead to significant socio-economic benefits while reducing 
public health risk.
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 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.
2.2
Study Objectives
2.2.1
Primary Objectives
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
Key secondary objectives of this study are as follows:

To evaluate the efficacy of SHP640 based on clinical resolution compared with PVP-I 
in the treatment of subjects with adenoviral conjunctivitis in the study eye at Visit 3 
(Day 6). 

To evaluate the efficacy of PVP-I based on adenoviral eradication (defined as 
negative cell culture-immunofluorescence assay [CC-IFA] in the study eye) 
compared with placebo in the treatment of subjects with adenoviral conjunctivitis in 
the study eye at Visit 2 (Day 3).

To evaluate the efficacy of SHP640 based on adenoviral eradication compared with 
placebo in the treatment of subjects with adenoviral conjunctivitis in the study eye at 
Visit 3 (Day 6).

To evaluate the efficacy of SHP640 based on adenoviral eradication compared with
PVP-I in the treatment of subjects with adenoviral conjunctivitis in the study eye at 
Visit 3 (Day 6). 

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
To evaluate the efficacy of PVP-I based on clinical resolution compared with placebo 
in the treatment of subjects with adenoviral conjunctivitis in the study eye at Visit 3 
(Day 6).
Adenoviral eradication is defined in Section 7.2.2.
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 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 resolution endpoints (bulbar conjunctival injection and 
watery conjunctival discharge) at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) 
and 5 (Day 12)
o
Global clinical score (sum of bulbar conjunctival injection and watery 
conjunctival discharge) 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)

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 PVP-I and placebo in 
the treatment of subjects with adenoviral conjunctivitis.
2.2.3
Exploratory Objectives
The exploratory objectives of this study are as follows: 

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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
SHP640-301 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 PVP-I 0.6% ophthalmic solution and to placebo in treating adenoviral 
conjunctivitis. 
Approximately 930 subjects ≥1 month of age will be randomized into the study at Visit 1 (Day 
1). Randomization will be stratified by age to maintain the randomization ratio among subjects 
<18 years and subjects ≥18 years. Subjects will be randomized 2:2:1 to receive either SHP640, 
PVP-I, or placebo within each stratum. 
Multiple subjects from the same household will be eligible to participate in the study (up to a 
prespecified household cap). 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 study medication 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 Day 3 (Visit 2), Day 6 (Visit 3), Day 8 (Visit 4), and Day 12 (Visit 5). All follow-up 
procedures will be conducted at Visit 5 (Day 12). The study will last up to 13 days. 
Figure 1 provides the study design.
Figure 1:
SHP640-301 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 80 sites across North America, South America, 
Asia/Pacific, and Europe.

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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed. If a subject is younger 
than the legal age of consent (per local laws), the subject's parent(s), guardian, or legally 
authorized representative will provide written informed consent; the subject will provide verbal 
or written assent as appropriate.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions (by the parent(s), guardian, or legally authorized representative, if 
applicable).
2. Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), 
guardian, or legally-authorized representative(s) informed consent (and assent, if 
applicable) to participate in the study.
3. Be ≥1 month of age at Visit 1. 
4. Have a positive RPS 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 RPS 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. Every attempt should be made 
to obtain a BCVA measurement in children and, if it is unobtainable, the decision as 
to whether the criterion is met will be at the investigator's discretion. 
8. Male, or non-pregnant, non-lactating female who agrees to comply with any 
applicable contraceptive requirements of the protocol or females of non-childbearing 
potential. 
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 

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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. Subjects from a household that has met the prespecified household enrollment cap
7. Have a history of ocular surgical intervention within ≤ 6 months prior to Visit 1 or 
planned for the period of the study.
8. Have a preplanned overnight hospitalization during the period of the study.
9. Have presence of any intraocular, corneal, or conjunctival ocular inflammation (e.g., 
uveitis, iritis, ulcerative keratitis), other than adenoviral conjunctivitis.
10. Have presence of corneal subepithelial infiltrates at Visit 1.
11. Have active or history of ocular herpes.
12. Have clinical signs or presence of ocular allergy or an ocular infection (e.g., bacterial, 
acanthamoeba, fungal or other ocular viral infection) currently or within ≤ 30 days of 
Visit 1 other than adenoviral conjunctivitis.
13. Be a known intraocular pressure (IOP) steroid responder, have a known history of 
glaucoma, be a glaucoma suspect, or have a known history of an elevated IOP > 21 
mmHg.
14. Have any known clinically significant optic nerve defects. 
15. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary 
to previous corneal trauma or dry eye syndrome; presence of any significant corneal 
opacity at Visit 1.
16. History of corneal transplant in either eye.
17. 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. 
18. Have used any topical ocular or systemic anti-virals within ≤ 7 days of enrollment. 
19. Have used any topical ocular NSAIDs within ≤ 1 day of enrollment.
20. Have used any topical ophthalmic steroids in the last ≤ 30 days.
21. Have used any inhaled or systemic corticosteroid agents within ≤ 14 days of Day 1. 
Stable (initiated ≥ 30 days prior to enrollment) use of inhaled and nasal 

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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.
22. Have used immunosuppressive agents within ≤ 14 days of Day 1.
23. Have used any topical ophthalmic products, including tear substitutes and, and over-
the-counter preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to 
discontinue all topical ophthalmic products for the duration of the study.
24. Have any significant ocular disease (eg, Sjogren's syndrome) or any uncontrolled 
systemic disease or debilitating disease (e.g., cardiovascular disease, hypertension, 
sexually transmitted diseases/infections, diabetes or cystic fibrosis), that may affect 
the study parameters, per Investigator’s discretion.
25. Have any autoimmune disease.
26. Any known history of immunodeficiency disorder or known active conditions 
predisposing to immunodeficiency, such as human immunodeficiency virus, hepatitis 
B or C, evidence of  active hepatitis A (antihepatitis A virus immunoglobulin M), or 
organ or bone marrow transplantation.
27. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device

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. Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period. If hormonal contraceptives are used they should be 
administered according to the package insert. Females of childbearing potential who are not 
currently sexually active must agree to use acceptable contraception, as defined below, if they 
become sexually active during the period of the study.
Female children and adolescent subjects should be either:

Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine pregnancy test at Visit 1. Females of 
childbearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Adult female subjects should be either:

Post-menopausal (12 consecutive months of spontaneous amenorrhea and age 51 years)

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
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 child-bearing 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

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. Note: If subject becomes 
sexually active during the study, they should use one of the other acceptable methods noted 
above in addition to the hormonal contraceptive.
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, treatment with an 
alternate therapy is in the best interest of subject for safety reasons). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for Visit 
5 are to be performed as completely as possible. Whenever possible, all discontinued subjects 
should also undergo the protocol-specified follow-up (proceed to Visit 5). Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded in the source 
documents. The reason for termination and the date of stopping investigational product must be 
recorded in the case report form (CRF) and source documents.
Subject numbers for subjects who discontinue will not be reused. 
4.4.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF. 
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol deviation

Withdrawal by subject

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
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
Inhaled or systemic corticosteroid agents
X
Stable use of inhaled and nasal 
corticosteroids
X
Allowed ≥30 days if no 
anticipated dose changes 
during the study
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-I) Ophthalmic Suspension, the comparator is 
0.6% PVP-I Ophthalmic Solution, and the placebo product is Placebo Ophthalmic Solution.
Each of these test products are manufactured aseptically and filled in sterile plastic ophthalmic 
bottles. The placebo contains 2 additional ingredients relative to the others: Benzalkonium 
Chloride, 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 three test products is 
provided in the current SHP640 Investigator's Brochure.
6.1.1
Masking the Treatment Assignment
The packaging, appearance, and labeling of the test products will match. Colorant will be added 
to the placebo to match the appearance of SHP640 and the PVP-I Ophthalmic Solution. 
Treatment assignment will be determined by the randomization schedule.
6.1.2
Commercially Obtained Investigational Product
Not Applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
An Interactive Response Technology (IRT) vendor will be used for this study to manage 
packaged investigational medicinal product (IMP) supply, IMP shipments, receipt of IMP at 
clinical sites, randomization of IMP to subjects, expiry tracking, and returns and accountability 
of IMP.  
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. 
Randomization will be stratified by age to maintain the randomization ratio among subjects <18 
years and subjects ≥18 years.  Subjects will be randomly assigned to receive SHP640, PVP-I 
0.6%, or placebo based on a 2:2:1 ratio [SHP640: PVP-I 0.6%: placebo] within the 
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Multiple subjects from the same household will be eligible to participate in the study (up to a 
prespecified household cap). 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. 
Individual subject treatment is automatically assigned by the IRT.
6.2.3
Dosing
Subjects will be instructed to instill 1 drop of study medication in each eye QID (with a 
minimum of 2 hours between doses) for 7 days.
Storage Requirements:
The study drug must be stored in a secure, refrigerated area accessible only to the investigator 
and his/her designees. The study drug will be administered only to subjects enrolled in the 
clinical study, in accordance with the conditions specified in this protocol.
Undispensed study drug should be stored under refrigeration at 2ºC-8ºC.
Dispensed study drug should be stored at room temperature below 30ºC. Study drug should be 
protected from freezing and exposure to strong light.
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.
The study drug 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 to keep 
subject on proper QID dosing schedule.  
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 documentation of and details related to 
the code break will be recorded by the IRT and the source documents. 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 
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6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack 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.
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 study drug 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 investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier and initials as permitted based on local laws 
on the investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
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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 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
Not Applicable.
6.4
Drug Accountability  
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All dispensed medication 
will be documented on the CRFs and/or other investigational product record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the mask of the study is not compromised.

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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 
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 are 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. Subjects must be between 80
and 100% compliant with dosing at each study visit. 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

RPS AdenoPlus test

Best corrected visual acuity

Slit lamp biomicroscopy

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o
Bulbar conjunctival injection evaluation
o
Watery conjunctival discharge evaluation

Non-dilated fundus examination

Urine pregnancy test (for women of childbearing potential)
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) 

Randomization

Ocular discomfort scale

Dispense and instill study medication in both eyes
The study drug bottle should be shaken well prior to use at each dosing.
In order to ensure QID dosing on Day 1 (with a minimum of 2 hours between doses); all 
assessments, randomization, and medication instillation on Day 1 must take place with sufficient 
time to allow all 4 Day 1 doses (prior to bedtime). 
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. Subjects must be between 80 
and 100% compliant with dosing at each study visit. 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 study medication within 12 hours of scheduled Study Visits.
Medication instillation should only be performed in-office if it is necessary to keep the subject 
on dosing schedule, and should be done once all other assessments are completed. Subjects who
instill medication less than 12 hours before study visits will be recorded as protocol deviations.
7.1.3
Visit 5 (End of Study or Early Termination)
Safety follow-up will be conducted at Visit 5 (the end of study visit). Visit 5 (Day 12) 
assessments will be performed as outlined in Table 1. Assessments should be performed in 
descending order as listed.
Subjects who discontinue the study and proceed to Visit 5 for early termination should have 
study medication 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
Patient demographic information will be collected at Visit 1. Date of Birth, 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 investigator must record all clinically or medically relevant information regardless of how 
much time has elapsed since the date of any diagnosis. Medical history will be classified as 
ocular or non-ocular by the investigator. History should include, but is not limited to: 

History of ocular diseases/conditions. 

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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
RPS AdenoPlus Test
The RPS AdenoPlus test will be performed at Visit 1 as outlined in Table 1. 
The RPS AdenoPlus test is an in-office test that allows for the detection of adenoviral antigens 
directly from human eye fluid. A small tear sample is transferred onto the AdenoPlus test, which 
confirms the presence of adenovirus and the viral form of conjunctivitis. 
Please refer to the Operations Manual for a detailed description of the RPS AdenoPlus Test and 
administration.
7.2.2
Efficacy
7.2.2.1
Clinical Resolution
Clinical resolution of adenoviral conjunctivitis is defined by 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 is defined as negative CC-IFA in the study eye.  CC-IFA will be 
conducted using conjunctival swab samples collected from the study eye. See the Laboratory 
Manual for further details.
7.2.3
Safety
Safety assessments will be performed in both eyes.
7.2.3.1
Slit Lamp Biomicroscopy
Slit lamp biomicroscopy (or hand held slit lamp) will be performed during the study as outlined 
in Table 1. 
Observations will be graded as Normal or Abnormal.  Abnormal findings will be described, and 
clinically significant abnormalities should be recorded in the source and on the 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:  

Cornea

Conjunctiva

Anterior Chamber

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
Iris

Lens

Lid
External examination and biomicroscopy will be performed using a slit lamp. Magnification will 
be consistent with standard clinical practice. The subject will be seated.
For infants and young children, if the above exams cannot be performed with a slit lamp or a 
hand held slit lamp, an external examination is to be conducted in accordance with 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). Observations will be graded as Normal or 
Abnormal. Abnormal findings will be described.
7.2.3.2
Non-dilated Fundus Examination
A non-dilated fundus examination will be performed in all patients 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

Retina

Macula

Choroid

Optic Nerve
Clinically significant changes should be recorded in the source and on the eCRF as an AE.
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.
7.2.3.3
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 patients 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, 

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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 
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. VA is to be measured using the same method at all visits in the same 
patient.
7.2.3.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.) Any AE that occurs after the first dose of 
study medication instillation will be considered a TEAE.
Adverse events may also be determined by the investigator during study examinations as 
mentioned in previous sections.
7.2.3.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
All bioanalytical assays for the study will be validated following FDA/ICH guidelines, based on 
the method's intended use. The clinical lab will only receive sample ID numbers and collection 
dates, the lab results will then be transferred to the central lab for data analysis. The lab will not 
receive any information on subject treatment assignment.
The following clinical laboratory assessments will be performed: 

Confirmatory Immunofluorescence Assay (CC-IFA): This test will be performed on
samples collected at all visits to determine the presence of adenovirus. 

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 inferior conjunctival cul-de-sac of each eye will be collected for all viral 
testing.

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7.2.3.6
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.
7.2.3.7
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 two items: eye discomfort and 
eye pain. Both eye discomfort and eye pain will be evaluated using a 0-10 scale. 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.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.

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

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

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

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8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO/Shire medical monitor 
within 24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see 
Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the CRO/Shire medical monitor using the details specified in the emergency 
contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
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. 

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8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject provides 
written informed consent (and assent, if applicable) until the defined follow-up period stated in 
Section 7.1.3 and must be reported to the Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and/or the clinical CRO is responsible for notifying the relevant regulatory 
authorities and 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 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
The sample size was estimated for the primary comparison and key secondary comparisons of 
SHP640 Ophthalmic Suspension to Placebo and to PVP-I by using nQuery Advisor 7.0. Subjects 
will be randomized 2:2:1 ratio to receive either SHP640 ophthalmic suspension, PVP-Iodine 
0.6%, or placebo within each stratum. 
A sample size of 350 subjects (140 subjects in each of SHP640 and PVP-I groups, 70 subjects in 
placebo) 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.
However, a sample size of 605 subjects (242 subjects in each of SHP640 and PVP-I groups, 121 
subjects in placebo) will ensure 90% power to compare SHP640 and PVP-I treatment groups 
assuming 31% and 18% subjects with clinical resolution respectively using Fisher’s Exact test at
two-sided 5% level of significance.
Therefore, 605 subjects will ensure 90% power for testing the hypothesis corresponding to the 
key secondary objective of comparing clinical resolution status in SHP640 vs PVP-I.  
All efficacy analyses will be based on the mITT population with post-baseline LOCF for the 
subjects who drop out before Visit 3 (Day 6).  To ensure 605 subjects in the mITT population, 
approximately 930 subjects will be randomized in this study (approximately 372 subjects in each 
of SHP640 and PVP-I groups, approximately 186 subjects in placebo). 
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 study medication and have a positive CC-IFA adenovirus test at 
baseline in the study eye.

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9.8
Efficacy Analyses
The analyses on primary, key secondary, and secondary efficacy endpoints will be performed on 
the mITT population and will be presented by treatment group. 
Additional sensitivity analyses may be conducted in the ITT population.
Efficacy data collected at Baseline (Visit 1 [Day 1]) will be used as the baseline for all efficacy 
analyses.
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 of clinical resolution (defined as absence of bulbar conjunctival 
injection and watery conjunctival discharge) in the study eye at Visit 3 (Day 6) 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 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.  A detailed analysis plan for primary analysis 
including additional methods to be used will be described in SAP.

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9.8.3
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints of this study are clinical resolution at Visit 3 (Day 6) and 
adenoviral eradication status (defined as negative cell culture-immunofluorescence assay [CC-
IFA]) in the study eye at Visits 2 (Day 3) and 3 (Day 6).
However, five hypotheses tests will be performed on mITT population (at Visit 3 (Day 6), unless 
otherwise specified) in order to achieve key secondary objectives of this study in following order 
only if statistical significance has been reached for the primary efficacy endpoint:
1.
Comparison of proportion of subjects achieving clinical resolution between 
SHP640 and PVP-I.
2.
Comparison of proportion of subjects achieving adenoviral eradication between 
PVP-I and Placebo at Visit 2 (Day 3)
3.
Comparison of proportion of subjects achieving adenoviral eradication between 
SHP640 and Placebo
4.
Comparison of proportion of subjects achieving adenoviral eradication between 
SHP640 and PVP-I.
5.
Comparison of proportion of subjects achieving clinical resolution between PVP-I 
and Placebo.
In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary 
hypotheses will be tested sequentially 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.

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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 sample size, mean, median, 
standard deviation, minimum, maximum and confidence intervals.  Binary endpoints will be 
summarized by sample size, proportions and confidence intervals.
Secondary efficacy endpoints are defined as follows:

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 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 resolution endpoints scores (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, 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, 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
9.8.5
Exploratory Efficacy Endpoints

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9.9
Safety Analyses
Safety data will be presented for the Safety Population by treatment group.
Safety data collected at baseline (Visit 1 / Day 1) will be used as the baseline value for safety 
analysis.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The 
number of events, incidence, and percentage of TEAEs will be calculated overall, by SOC, by 
preferred term, and by treatment group. Treatment-emergent adverse events will be further 
summarized by severity and relationship to investigational product. Adverse events related to 
investigational product, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized and listed.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or 
non-ocular AE.
The following safety endpoints will be descriptively summarized by treatment group at each 
measured time point:

Slit Lamp Biomicroscopy

Non-dilated Fundus Examination

Best Corrected Visual Acuity (BCVA)

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. 
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, 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.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of

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

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protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, 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 (paper or electronic) 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 AdenoPlus test results.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) will check the CRF 
entries against the source documents. The consent form includes a statement by which the

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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 
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.

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

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The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP640; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, other information (eg, initials and 
date of birth if the local law permits) may also be collected and used to assist the sponsor to 
verify the accuracy of the data (eg, to confirm that laboratory results have been assigned to the 
correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries 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 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on

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

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11.
REFERENCES
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.
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.
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.

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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.
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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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).