Conditions: Adenoviral Conjunctivitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 219
Healthy volunteers: no

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

Detailed description:

Arms:
arm 1: Participants will receive one drop of SHP640 (0.1 percent \[%\] dexamethasone and 0.6% PVP-I) ophthalmic suspension in each eye 4 times daily (QID) for 7 days. arm 2: Participants will receive one drop of 0.6% PVP-I ophthalmic solution in each eye QID for 7 days. arm 3: Participants will receive one drop of placebo ophthalmic solution in each eye QID for 7 days.

Interventions: intervention 1: SHP640 intervention 2: PVP-I 0.6% intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will receive one drop of SHP640 (0.1 % dexamethasone and 0.6% PVP-I) ophthalmic suspension in each eye QID (with a minimum of 2 hours between doses) for 7 days. intervention 2: Participants will receive one drop of PVP-I ophthalmic solution in each eye QID (with a minimum of 2 hours between doses) for 7 days. intervention 3: Participants will receive one drop of placebo ophthalmic solution in each eye QID (with a minimum of 2 hours between doses) for 7 days.

Protocol document:
SAP_004.pdf: 
Protocol SHP640-301 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
SHP640-301 
Protocol Title: 
A Phase 3, Multi-center, Randomized, Double-Masked 
Study to Evaluate the Clinical Efficacy and Safety of 
SHP640 (PVP-Iodine 0.6% and Dexamethasone 0.1%) 
Ophthalmic Suspension Compared to PVP-Iodine and 
Placebo in the Treatment of Adenoviral Conjunctivitis 
Drug: 
SHP640 
Sponsor:  
Shire 
300 Shire Way, Lexington, MA 02421 USA 
Version No. and Date 
Protocol Amendment 3: 13 December, 2017 
 
Version No: 
Document History 
Description of Update 
Author(s) 
Effective Date 
Version 1.0 
Final Version 
 
24 June, 2019 
 


Protocol SHP640-301 
 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 2 
ABBREVIATIONS .................................................................................................................... 4 
1. 
INTRODUCTION .......................................................................................................... 5 
2. 
STUDY DESIGN ........................................................................................................... 6 
2.1 
General Study Design ..................................................................................................... 6 
2.2 
Randomization ................................................................................................................ 6 
2.3 
Masking .......................................................................................................................... 7 
2.4 
Schedule of Assessments ................................................................................................ 7 
2.5 
Determination of Sample Size ........................................................................................ 9 
2.6 
Multiplicity Adjustments for Type I Error Control ...................................................... 10 
3. 
OBJECTIVES .............................................................................................................. 11 
3.1 
Primary Objective ......................................................................................................... 11 
3.2 
Secondary Objective ..................................................................................................... 11 
3.3 
Exploratory Objective .................................................................................................. 12 
4. 
SUBJECT POPULATION SETS ................................................................................. 13 
4.1 
Screened Population ..................................................................................................... 13 
4.2 
Safety Population ......................................................................................................... 13 
4.3 
Intent to Treat (ITT) Population ................................................................................... 13 
4.4 
Modified Intent to Treat (mITT) population ................................................................ 13 
5. 
SUBJECT DISPOSITION ........................................................................................... 14 
6. 
PROTOCOL DEVIATIONS ........................................................................................ 15 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 16 
8. 
EXTENT OF EXPOSURE ........................................................................................... 17 
9. 
PRIOR AND CONCOMITANT MEDICATION ........................................................ 18 
10. 
EFFICACY ANALYSES ............................................................................................. 19 
10.1 
Study Eye Designation ................................................................................................. 19 
10.2 
Primary, Key Secondary and Secondary Efficacy Endpoints and Analysis ................ 19 
10.3 
Exploratory Efficacy Endpoints and Analyses ............................................................. 21 
11. 
SAFETY ANALYSES ................................................................................................. 22 


Protocol SHP640-301 
 
 
 
11.1 
Adverse Events ............................................................................................................. 22 
11.2 
Other Safety Variables ................................................................................................. 23 
12. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES ................................................................................................................. 24 
13. 
OTHER ANALYSES ................................................................................................... 25 
14. 
INTERIM ANALYSIS ................................................................................................. 26 
15. 
DATA MONITORING/REVIEW COMMITTEE ....................................................... 27 
16. 
COMPUTER METHODS ............................................................................................ 28 
17. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ....................................... 29 
18. 
DATA HANDLING CONVENTIONS ....................................................................... 30 
18.1 
General Data Reporting Conventions ........................................................................... 30 
18.2 
Study Visits and Windows ........................................................................................... 30 
18.3 
Derived Efficacy Endpoints ......................................................................................... 30 
18.4 
Repeated or Unscheduled Assessments of Safety Parameters ..................................... 31 
18.5 
Missing Date of Investigational Product ...................................................................... 31 
18.6 
Missing Date Information for Prior or Concomitant Medications ............................... 32 
18.6.1 Incomplete Start Date ............................................................................................ 32 
18.6.2 Incomplete Stop Date............................................................................................. 32 
18.7 
Missing Date Information for Adverse Events ............................................................. 33 
18.7.1 Incomplete Start Date ............................................................................................ 33 
18.8 
Missing Severity Assessment for Adverse Events ....................................................... 33 
18.9 
Missing Relationship to Investigation Product for Adverse Events ............................. 34 
19. 
REFERENCES ............................................................................................................. 35 
20. 
APPENDIX .................................................................................................................. 36 
20.1 
Example SAS Code for Generating Descriptive Statistics ........................................... 36 
21. 
TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS .................... 37 
List of Tables 
Table 1 
Schedule of Assessments ......................................................................................... 8 
 List of Figures 
Figure 1: 
SHP640-301 Study Design ...................................................................................... 6 


Protocol SHP640-301 
 
 
 
ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
CC-IFA 
cell culture-immunofluorescence assay 
CFU 
colony forming unit 
CI 
confidence interval 
CRF 
case report form 
eCRF 
electronic case report form 
GCS 
Global clinical score 
HSV 
Herpes Simplex Virus 
IRT 
interactive response technology 
ITT 
Intent To Treat 
LOCF 
last observation carried forward 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent To Treat 
PT 
Preferred Term 
PVP-I 
povidone-iodine 
qPCR 
quantitative polymerase chain reaction 
RPS 
Rapid Pathogen Screening, Inc. 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SE 
standard error 
TEAE 
treatment-emergent adverse event 
VBR 
Validated Bulbar Redness 
WHO-DD 
World Health Organization – Drug Dictionary 
WOCF 
worst observation carried forward 


Protocol SHP640-301 
 
 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy and safety data as described in the final study protocol 
amendment 4.0 dated April 5, 2019. Specifications for tables, figures, and listings are 
contained in a separate document.   


Protocol SHP640-301 
 
 
 
2. 
STUDY DESIGN  
2.1 
General Study Design 
SHP640-301 is a global, multi-center, randomized, double-masked, parallel group, placebo 
controlled study designed to demonstrate the safety and efficacy of SHP640 (povidone-iodine 
[PVP-I] 0.6% and dexamethasone 0.1%) ophthalmic suspension compared to PVP-I 0.6% 
ophthalmic solution and to placebo in treating adenoviral conjunctivitis. 
Once screening and baseline assessments are complete and subjects are confirmed eligible to 
enroll in the study, subjects will be randomized, and investigational product will be 
administered on the same day (Day 1). The first dose will be administered by site staff on Day 
1, and thereafter subjects will administer 1 drop in each eye 4 times a day (QID) for 7 days. 
Additional visits will occur on 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 15 days. 
 
Figure 1 provides the study design. 
 
Figure 1: 
SHP640-301 Study Design 
 
2.2 
Randomization 
 
This is a double-masked, placebo-controlled study. The actual treatment given to individual 
subject is determined by a randomization schedule. 
 
Subject numbers are assigned to all subjects as they consent to take part in the study. Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation. 
 
The randomization number represents a unique number corresponding to investigational 
product allocated to the subject, once eligibility has been determined. Individual subject 
treatment is automatically assigned by the interactive response technology (IRT). 
 
 


Protocol SHP640-301 
 
 
 
Approximately 540 subjects will be randomized into the study at Visit 1 (Day 1). 
Randomization will be stratified by age strata: subjects < 6 years, 6 to <18 years and ≥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. 
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 (switching of the assigned treatment) or potential treatment unmasking. 
Dynamic balanced randomization (Pocock and Simon, 1975) will be used in this study to 
maintain the randomization ratio within each stratum. The randomization will be done 
centrally.  
 
2.3 
Masking  
This is a double-masked study.  The packaging, appearance, and labeling of the test products 
will match. Colorant will be added to the placebo to match the appearance of SHP640 
ophthalmic suspension and the PVP-I ophthalmic solution. 
 
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor as soon as possible after the 
unmasking occurs. 
 
In the event that the treatment assignment is broken, the date and person who broke the code 
will be recorded by the IRT and the reason for breaking will be recorded on the electronic 
case report form (eCRF). Upon breaking the mask, the subject is withdrawn from the study, 
but should complete Visit 5 (the end of study visit) assessments for safety purposes. Any 
code-breaks that occur must be reported to the Sponsor medical monitor. 
 
The final unmasking of the data will occur after all the data has been received, appropriately 
reviewed and checked, and the database has been locked per Shire's SOPs.  Final analyses 
will be performed after the official database release using the unmasked data. 
 
2.4 
Schedule of Assessments  
 


Protocol SHP640-301 
 
 
 
 below presents a schematic of the study design. 
 
 


Protocol SHP640-301 
 
 
 
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) 
+1 Day 
Visit 3 
(Day 6) 
Visit 4 
(Day 8) 
+1 Day 
Visit 5b 
(Day 12) 
+2 Days 
Informed consent/assenta 
X 
 
 
 
 
Inclusion/exclusion criteriaa 
X 
 
 
 
 
Medical history  
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
Urine pregnancy test 
Xc 
 
 
 
Xc 
Ocular Discomfort Scale 
X 
X 
X 
X 
X 
Best corrected visual acuity 
X 
X 
X 
X 
X 
Slit lamp biomicroscopy 
X 
X 
X 
X 
X 
Bulbar 
conjunctival 
injection 
evaluation 
X 
X 
X 
X 
X 
Watery 
conjunctival 
discharge 
evaluation 
X 
X 
X 
X 
X 
AdenoPlus® test 
Xd  
 
 
 
 
Conjunctival swab for viral culturee 
Xl 
Xf 
Xf 
Xf 
Xf 
Non-dilated/ 
dilated 
fundus 
examinationg 
X 
 
 
 
X 
Randomizationh 
X 
 
 
 
 
Dispense investigational producti 
X 
 
 
 
 
Instill investigational product 
Xj 
Xj 
Xj 
 
 
Collect investigational product 
 
 
 
X 
Xb 
Compliance assessment 
 
X 
X 
X 
Xb 
Drug accountability 
 
 
 
X 
Xb 


Protocol SHP640-301 
 
 
 
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) 
+1 Day 
Visit 3 
(Day 6) 
Visit 4 
(Day 8) 
+1 Day 
Visit 5b 
(Day 12) 
+2 Days 
Adverse events 
Xk 
X 
X 
X 
X 
Study completion 
 
 
 
 
X 
CC-IFA= cell culture-immunofluorescence assay; HSV= herpes simplex virus; qPCR= quantitative polymerase 
chain reaction;  
a Informed consent and confirmation of inclusion/exclusion criteria can be conducted on Day -1; 
Inclusion/Exclusion must be re-confirmed on Day 1. 
b If investigational product is discontinued, regardless of the reason, all discontinued subjects should proceed to 
Visit 5 whenever possible. Subjects that discontinue the study and proceed to Visit 5 should perform all Visit 5 
assessments as well as drug return, compliance and accountability. 
c Women of childbearing potential, prior to enrollment and at exit from the study. 
d If not previously conducted within 24 hours of Visit 1 (Day 1). 
e One swab sample from inferior conjunctival cul-de-sac of each eye will be collected for all viral testing. If the 
CC-IFA test is positive, qPCR will be performed. Adenoviral serotyping will be conducted at baseline only. 
f Conjunctival swab samples MUST be taken at least 12 hours after the last dose of investigational product at 
Visits 2, 3, 4 and ET, if applicable. 
g If a non-dilated fundus exam is not feasible, a dilated examination should be conducted. For each subject, the 
exam should be conducted the same way (either non-dilated or dilated) at both Visit 1 and Visit 5 (or ET).  
h All assessments, randomization, and investigational product instillation on Day 1 must take place with 
sufficient time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses) 
i The investigational product bottle should be shaken well prior to use at each dosing. The first dose will be 
administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a day for 
7 days. 
j Investigational product instillation should only be performed in-office if it is necessary. 
k Monitoring for adverse events will begin after informed consent is obtained. Information about unresolved AEs 
at the time of study exit (eg, resolution status, resolution date, treatment received for AE) and related information 
(eg, data from any assessments conducted to follow up on the status of unresolved AE) for a period of up to 14 
days after subject exit may be collected by the Sponsor. Corneal AEs that are ongoing at the end of study visit 
should be followed up by the site until resolution or stabilization and all related information should be collected 
in the CRF. 
l This sample will be used for baseline HSV testing for all subjects. For subjects <2 months of age, testing will 
also be conducted using the same sample for chlamydia and gonorrhea detection. 
 
 
2.5 
Determination of Sample Size 
The sample size was estimated for the primary comparison and key secondary comparisons of 
SHP640 ophthalmic suspension to placebo and to PVP-I, respectively, by using nQuery 
Advisor 7.0. Subjects will be randomized in a 2:2:1 ratio to receive either SHP640 ophthalmic 
suspension, PVP-I, or placebo within each stratum. 
 


Protocol SHP640-301 
 
 
 
The primary efficacy endpoint is clinical resolution (defined as absence of bulbar conjunctival 
injection and watery conjunctival discharge) in the study eye at Visit 3 (Day 6). The null 
hypothesis to be tested is that there is no difference in proportion of subjects with clinical 
resolution in the study eye between SHP640 ophthalmic suspension and placebo with the 
alternative of the non-zero difference in the proportion with clinical resolution between them. 
 
A sample size of 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.  
 
The first key secondary efficacy comparison is to compare the proportion of subjects 
achieving at least 2 points reduction from baseline in global clinical score (GCS) at Visit 3 
(Day 6) between SHP640 and PVP-I. The null hypothesis to be tested is that there is no 
difference in proportion of subjects with at least 2 points reduction from baseline in GCS in 
the study eye between SHP640 ophthalmic suspension and PVP-I with the alternative of the 
non-zero difference in the proportion with at least 2 points reduction from baseline in GCS 
between them. 
 
A sample size of 350 subjects (140 subjects in each of SHP640 and PVP-I groups, 70 subjects 
in placebo) will also ensure 98% power to compare SHP640 and PVP-I treatment groups 
assuming 90% and 70% subjects with at least 2 points reduction from baseline in global 
clinical score at Visit 3 (Day 6) respectively using Fisher’s Exact test at two-sided 5% level of 
significance. 
The assumed proportions of subjects with clinical resolution in the three treatment arms are 
based on response rates observed in FST100-AVC-004 with a dropout rate of approximately 
6% prior to Visit 3 in FST100-AVC-004 modified Intent-to-Treat (mITT) population which 
excluded subjects with no post baseline data. The dropout rate would become approximately 
8% if FST100-AVC-004 mITT population included subjects with no post baseline data. 
 
All efficacy analyses will be based on the mITT population (refer to Section 4.4 for the 
definition of mITT). Assuming a 35% reduction from randomized to the mITT, approximately 
540 subjects (i.e. approximately 216 in each of SHP640 and PVP-I group and approximately 
108 in placebo group) will be randomized in this study.  
 
2.6 
Multiplicity Adjustments for Type I Error Control 
 
Multiplicity adjustment is not applicable and no hypothesis testing will be conducted for any 
efficacy endpoints since the study was terminated early. 
 
 


Protocol SHP640-301 
 
 
 
3. 
OBJECTIVES 
 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical 
resolution (defined as absence of bulbar conjunctival injection and watery conjunctival 
discharge) compared with placebo in the treatment of subjects with adenoviral conjunctivitis 
in the study eye at Visit 3 (Day 6). 
 
3.2 
Secondary Objective 
Key secondary objectives of this study are as follows: 
 
 To evaluate the efficacy of SHP640 based on ≥2 point reduction from baseline on the 
global clinical score 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]) 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 ≥2 point reduction from baseline on global 
clinical score 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 12) 


Protocol SHP640-301 
 
 
 
o Individual clinical signs (bulbar conjunctival injection and watery conjunctival 
discharge) at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) 
o The global clinical score (GCS) (sum of bulbar conjunctival injection and 
watery conjunctival discharge) and change from baseline in the global clinical 
score at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) 
o At least 2 point reduction from baseline on global clinical score at Visits 2 
(Day 3), 4 (Day 8) and 5 (Day 12) 
o Modified clinical resolution, defined as a global clinical score of 0 or 1, at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) 
o Expanded clinical resolution, defined as a global clinical score of 0, 1, or 2 
with neither injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 
(Day 6), 4 (Day 8) and 5 (Day 12) 
o Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 
6), 4 (Day 8), and 5 (Day 12)  
 To assess the status of cross-over infection (as assessed by CC-IFA) to a subject’s 
fellow eye at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with 
only 1 infected eye at baseline. 
 To evaluate the safety and tolerability (including local tolerability) of SHP640 
compared to PVP-I and placebo in the treatment of subjects with adenoviral 
conjunctivitis. 
 
3.3 
Exploratory Objective 
The exploratory objectives of this study are as follows: 
 


Protocol SHP640-301 
 
 
 
4. 
SUBJECT POPULATION SETS 
 
4.1 
Screened Population 
The Screened Population will consist of all subjects who have provided written informed 
consent. 
4.2 
Safety Population 
The Safety Population will consist of all subjects who receive at least one dose of 
investigational product. 
4.3 
Intent to Treat (ITT) Population 
The ITT Population will include all randomized subjects. 
4.4 
Modified Intent to Treat (mITT) population 
The mITT Population consists of a subset of the ITT population who receive at least one dose 
of investigational product and have a positive CC-IFA adenovirus test at baseline in the study 
eye. 
Analyses conducted using the ITT and mITT will be based upon the treatment assigned while 
analyses conducted using the Safety Analysis Set will be based upon the treatment received. 


Protocol SHP640-301 
 
 
 
5. 
SUBJECT DISPOSITION 
A listing of all Screen Failures (ie, subjects who were screened but not randomized) will be 
presented along with reasons for screen fail.   
The number of subjects included in each subject population (ie, Screened, Safety, ITT and 
mITT) will be summarized by randomized treatment group, age strata and overall except for 
the Screened Set, which will be summarized for all subjects only. 
 
The number and percentage of subjects who completed and prematurely discontinued during 
the Double-masked Evaluation Phase will be presented for each treatment group, age strata 
and overall.  Reasons for premature discontinuation from the Double-masked Evaluation 
Phase as recorded on the termination page of the eCRF will be summarized (number and 
percentage) by treatment group, age strata and overall.  All percentages will be based on the 
number of subjects in the ITT Population.  
 
A listing of disposition will be provided for all subjects. All subjects who prematurely 
discontinued during the Double-masked Evaluation Phase will be listed by discontinuation 
reason. 


Protocol SHP640-301 
 
 
 
6. 
PROTOCOL DEVIATIONS 
  
Protocol deviations will be recorded by the site monitors separately from the clinical database. 
Protocol deviations will be listed for subjects in the ITT Population. 
 


Protocol SHP640-301 
 
 
 
7. 
DEMOGRAPHIC AND OTHER BASELINE 
CHARACTERISTICS 
 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for Safety population, ITT population and mITT population.  
 
The following demographic characteristics will be summarized in the following order in the 
tables: age, age strata (< 6 years [0-27 days], 6 to <18 years and ≥18 years), sex, ethnicity and 
race. In addition, iris color in the study eye will be summarized.  
 
Percentages will be based on the total number of subjects in each treatment group. 
 
A listing will be generated for demographic and baseline characteristics for the ITT 
Population with flags indicating whether the subject is in the Safety Population and mITT 
population. 
A listing of ocular and non-ocular medical history will be provided for the Safety Population. 


Protocol SHP640-301 
 
 
 
8. 
EXTENT OF EXPOSURE  
Exposure to double-masked investigational product for the Safety Population will be 
summarized in terms of treatment duration, which is calculated as the number of days from 
the date of first dose of double-masked investigational product taken to the date of the last 
dose of double-masked investigational product taken, inclusively, and irrespective of any 
investigational product interruption(s).  Descriptive statistics will be presented by treatment 
group and overall.  
Listings of investigational product exposure and study drug withheld will be provided for all 
subjects in the Safety Population. 
 


Protocol SHP640-301 
 
 
 
9. 
PRIOR AND CONCOMITANT MEDICATION  
All medications will be coded using the World Health Organization – Drug Dictionary 
(WHO-DD) Version 01SEP2016 categorized by anatomical therapeutic class (ATC) and 
preferred term. Medications/therapies/procedures will be further categorized as ocular or non-
ocular by the investigator based on the indication for which the medication/therapy/procedure 
was used. 
 
Prior medication/therapy/procedure is defined as any medication/therapy/procedure with a 
start date prior to the date of the first dose of investigational product.  
 
Concomitant medication/therapy is defined as any medication/therapy with a start date prior 
to the date of the first dose of investigational product and continuing after the first dose of 
investigational product or with a start date between the dates of the first and last doses of 
investigational product, inclusively. Concomitant procedure is defined as any procedure with 
a start date between the dates of the first and last doses of investigational product, inclusively. 
Any medication/therapy/procedure with a start date after the date of the last dose of 
investigational product will not be considered a concomitant medication/therapy/procedure. 
Medications/therapy/procedure will be further categorized as ocular or non-ocular by the 
investigator based on the indication for which the medication/therapy/procedure was used. 
 
Medications can be considered both as prior and concomitant medication.   
All prior and concomitant medication will be listed. Prior and concomitant therapy/procedure 
will also be listed. Imputed dates (see Section 18.6 for imputation rules) will be marked in the 
listings. 
Medication/therapy/procedure with a start date after the date of the last dose of investigational 
product will also be listed.  
 
 


Protocol SHP640-301 
 
 
 
10. 
EFFICACY ANALYSES 
 
All efficacy summaries will be based on the mITT unless stated otherwise.  Baseline for all 
efficacy analyses is defined as the value for the efficacy assessment at Visit 1.   
All confidence intervals (CIs) will be 2-sided 95% CIs.  
All efficacy analyses will be conducted according to the treatment assigned. 
All efficacy endpoints will be listed in the ITT Population. The listing will include a flag to 
indicate whether the subject is in mITT. 
10.1 
Study Eye Designation 
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a 
score of at least 1 for both watery conjunctival discharge and bulbar conjunctival redness at 
baseline: 
 
 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 (refer to Section 3.2) at baseline. 
If both eyes have the same global clinical score at baseline, then the study eye will be 
the right eye. 
 For subjects with both eyes eligible with a positive 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. 
 
The eye other than the study eye is considered the fellow eye in all safety and efficacy 
analyses. 
10.2 
Primary, Key Secondary and Secondary Efficacy Endpoints and Analysis 
Primary efficacy Endpoint: 
 The clinical resolution status of adenoviral conjunctivitis at Visits 3 (Day 6) in the 
study eye 
 
Key secondary efficacy endpoint: 
 ≥2 point reduction from baseline on GCS at Visit 3 (Day 6) in the study eye  
 Adenoviral eradication status (defined as negative cell culture-immunofluorescence 
assay [CC-IFA]) at Visits 2 (Day 3) and 3 (Day 6) in the study eye 
 
Secondary efficacy endpoints are defined as follows: 


Protocol SHP640-301 
 
 
 
 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 signs score (bulbar conjunctival injection and watery 
conjunctival discharge) and change from baseline at Visits 2 (Day 3), 3 (Day 6), 4 
(Day 8) and 5 (Day 12) in the study eye 
 The global clinical score (as defined as the sum of bulbar conjunctival injection and 
watery conjunctival discharge) and change from baseline in the global clinical score at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the study eye 
 At least 2 point reduction from baseline on global clinical score at Visits 2 (Day 3), 4 
(Day 8) and 5 (Day 12) in the study eye 
 Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 
2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the study eye 
 Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with 
neither injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 6), 4 
(Day 8) and 5 (Day 12) in the study eye 
 Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 
(Day 8), and 5 (Day 12) in the study eye 
 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 
 
 
No hypothesis testing will be conducted for the efficacy endpoints. Clinical resolution status, 
≥2 point reduction from baseline on GCS and adenoviral eradication status efficacy endpoints 
will be summarized by treatment group using descriptive statistics at each assessment visit in 
the mITT Population. Clinical resolution status will also be summarized by treatment group 
using descriptive statistics at each assessment visit in the ITT Population. These binary 
endpoints will be summarized by number of subjects (n), frequency, proportion and two-sided 
95% CI (exact CI for binominal proportion). Other secondary endpoints will not be 
summarized by treatment group.  
 
No hypothesis testing will be conducted for any efficacy endpoints. 
 
All efficacy endpoints will be listed in ITT with a flag indicating whether the subject is in 
mITT population.  
 
Appendix 20.1 shows example SAS code for generating descriptive statistics: 
 


Protocol SHP640-301 
 
 
 
10.3 
Exploratory Efficacy Endpoints and Analyses  


Protocol SHP640-301 
 
 
 
11. 
SAFETY ANALYSES 
The safety analysis will be performed using the Safety Population.  Safety variables include 
adverse events (AEs, including local tolerability), slit lamp biomicroscopy, non-
dilated/dilated fundus exam, red reflex exam, best corrected visual acuity (BCVA), and urine 
pregnancy testing (for females of childbearing potential) variables. Safety data collected at 
baseline (Visit 1) will be used as the baseline value for safety analysis. All safety analyses 
will be conducted according to the treatment the subject actually received.  
11.1 
Adverse Events  
 AEs will be coded using MedDRA version 19.1. Any AE that occurs after the first dose of 
investigational product instillation will be considered a treatment- emergent adverse event 
(TEAE). 
 
An overall summary of the number of subjects with TEAEs will be presented, including the 
number and percentage of subjects with any TEAEs, ocular TEAEs, non-ocular TEAEs, 
TEAEs leading to death, serious TEAEs, TEAEs related to investigational product and 
TEAEs leading to discontinuation of investigational product as well as the total number of 
events in each category. 
 
The number and percentage of subjects reporting TEAEs in each treatment group and across 
all subjects will be tabulated by System Organ Class (SOC) and Preferred Term (PT) as well 
as by SOC, PT, and maximum severity.  TEAEs considered related to investigational product 
will also be summarized by SOC and PT. If more than 1 AE occurs with the same SOC/PT 
for the same subject, then the subject will be counted only once for that SOC/PT using the 
most severe and most related occurrence for the summarization by severity and by 
relationship to investigational product, respectively. The incidence of common TEAEs ( 5% 
of subjects in any treatment group) will also be summarized by SOC and PT. Serious TEAEs, 
TEAEs leading to discontinuation of investigational product and TEAEs leading to death, will 
be summarized by SOC, PT and treatment group and across all subjects. The number and 
percentage of subjects reporting local tolerability TEAEs (overall, related to IP and not related 
to IP) in each treatment group and across all subjects will also be tabulated by SOC and PT. 
PTs that are considered to be local tolerability AEs will be provided by global drug safety 
(GDS) before database lock. Separate tables will be generated for ocular TEAEs and non-
ocular TEAEs. For all above tables, ocular TEAEs will be summarized at subject level and 
also by study eye, fellow eye and both eyes.  
 
Listings of all TEAEs will be provided by subject. 
 
Pre-treatment events (captured on the AE form that occurred prior to the first dose of 
investigational product) will be listed by subject but not tabulated. 
 
Imputed dates, severity and relationship (see Section 18.7, 18.8 and 18.9 respectively for 
imputation rules) to investigational product will be marked in the listings. 


Protocol SHP640-301 
 
 
 
 
11.2 
Other Safety Variables 
The following safety measures will be descriptively summarized by study eye and fellow eye 
and by treatment group and across all subjects at each visit: 
 Best corrected visual acuity (BCVA, logMAR scoring) and change from baseline 
BCVA 
 Slit lamp biomicroscopy (normal, abnormal – not clinically significant, abnormal – 
clinically significant) for 6 anatomic anterior segment regions: lids, conjunctiva, 
cornea, iris, anterior chamber and lens  
 Non-dilated/ Dilated Fundus examination (normal, abnormal – not clinically 
significant, abnormal – clinically significant) for 3 anatomic posterior segment 
regions: vitreous,  optic nerve and macula 
 Red reflex examination (normal, abnormal– not clinically significant, abnormal – 
clinically significant) for infants and small children in whom a fundus examination 
cannot be done 
Continuous endpoints will be summarized by number of subjects (n), mean, median, SD, SE, 
minimum and maximum. Binary endpoints will be summarized by number of subjects (n), 
frequency and percentage. 
 
BCVA/change from baseline BCVA and slit lamp biomicroscopy at each visit as well as non-
dilated/ dilated fundus examination (or red reflex exam for infants and small children in 
whom a fundus examination cannot be done) and pregnancy test results at visits 1 and 5/early 
termination will be provided by subject in Safety Population in data listings. A by subject 
listing will also be generated for chlamydia and gonorrhea results at Visit 1 in Safety 
Population in subjects less than 2 month of age and for Herpes Simplex Virus (HSV) at Visit 
1 in Safety Population. 


Protocol SHP640-301 
 
 
 
12. 
CLINICAL PHARMACOKINETIC AND 
PHARMACODYNAMIC ANALYSES 
N/A. 


Protocol SHP640-301 
 
 
 
13. 
OTHER ANALYSES  
 
There is no other analysis planned for this study.  
 


Protocol SHP640-301 
 
 
 
14. 
INTERIM ANALYSIS 
There is no interim analysis in this study. 


Protocol SHP640-301 
 
 
 
15. 
DATA MONITORING/REVIEW COMMITTEE 
There is no data monitoring committee for this study.  
 


Protocol SHP640-301 
 
 
 
16. 
COMPUTER METHODS  
Statistical analyses will be performed using Version 9.2 (or higher) of SAS on a suitably 
qualified environment.   


Protocol SHP640-301 
 
 
 
17. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Since a decision has been made to early terminate the trial, an abbreviated Clinical Study 
Report (CSR) will be generated, which will contain a full report of information related to 
safety and abbreviated summary of efficacy evaluation. The majority of the efficacy analyses 
outlined in section 9.8, efficacy analysis section of the protocol will not be conducted. No 
hypothesis testing will be performed on any of the efficacy endpoint. Only descriptive 
statistics will be generated for clinical resolution status, ≥2 point reduction from baseline on 
GCS and adenoviral eradication status as outlined in section 10.2 of this SAP. 


Protocol SHP640-301 
 
 
 
18. 
DATA HANDLING CONVENTIONS 
18.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics: number of 
subjects (n), mean, median, SD, minimum, maximum unless otherwise specified.  Categorical 
and count variables will be summarized by the number of subjects (n), frequency and the 
percent of subjects in each category unless otherwise specified.  Percentages will be presented 
with one decimal point.  
See TFLs4Shire for rules on the number of decimal places to present data and p-values.  
18.2 
Study Visits and Windows 
CRF visits will be used in all summary tables and listings.  
 
Study day will be calculated as follows: 
 If the assessment date is on or after the date of first instillation:  
Study day = assessment date – first dosing date + 1 
 If the assessment date is before the date of first instillation: 
Study day = assessment date – first dosing date 
 
18.3 
Derived Efficacy Endpoints  
Clinical resolution is defined as absence of bulbar conjunctival injection and watery 
conjunctival discharge. Bulbar Conjunctival Injection will be assessed based on a 0-4 scale 
which uses pictures from the Validated Bulbar Redness (VBR) Scale. Watery Conjunctival 
Discharge will be assessed based on a 0-3 scale. For both bulbar conjunctival injection and 
watery conjunctival discharge, 0 score indicates normal or none and a higher score indicates a 
higher severity of the clinical sign. A 0 sum of bulbar conjunctival injection score and watery 
conjunctival discharge score represents reaching clinical resolution. Any non 0 sum means not 
reaching clinical resolution. If either individual score is missing, clinical resolution status will 
be set to missing. 
Adenoviral eradication is defined as negative CC-IFA (indeterminate CC-IFA result is 
considered negative CC-IFA). Positive CC-IFA is considered not reaching adenoviral 
eradication. If an eye has missing CC-IFA result at baseline, the eye will be assumed to be 
CC-IFA negative at baseline for determination of the study eye. 
Global clinical score is defined as the sum of bulbar conjunctival injection score and watery 
conjunctival discharge score. If either individual score is missing, global clinical score will be 
set to missing. 


Protocol SHP640-301 
 
 
 
Modified clinical resolution is defined as a global clinical score of 0 or 1. All other scores are 
considered not reaching modified clinical resolution. If either individual score is missing, 
modified clinical resolution status will be set to missing. 
 
Expanded clinical resolution is defined as a global clinical score of 0, 1, or 2 with neither 
bulbar conjunctival injection score nor watery conjunctival discharge score having a score of 
2. Otherwise, the subject is considered not reaching expanded clinical resolution. If either 
individual score is missing, expanded clinical resolution status will be set to missing. 
 
Time to clinical resolution will be derived based upon assessments at Visits 2 (Day 3), 3 (Day 
6), 4 (Day 8), and 5 (Day 12) in the study eye. Time to clinical resolution will equal to the 
study day corresponding to the visit when the subject first reaches clinical resolution in the 
study eye. 
 
Cross over infection status will be assessed by CC-IFA results as follows: 
 
Scenario 
Cross-over Infection Status at 
Post Baseline Visit 
Both eyes CC-IFA positive at baseline 
Not applicable 
Only one eye CC-IFA 
positive at baseline 
The other eye CC-IFA 
positive at post baseline visit 
Yes 
The other eye CC-IFA 
negative at post baseline visit 
No 
Both eyes CC-IFA negative at baseline 
Not applicable 
 
Ocular discomfort total score (in the version for adult and older children) is defined as the 
sum of eye pain score, the feeling that something was in your eye score and itching score. If 
any individual score is missing, then ocular discomfort total score will be set to missing. 
18.4 
Repeated or Unscheduled Assessments of Safety Parameters  
Assessments obtained on the scheduled CRF visits will be included in summary tables. 
Additional repeated or unscheduled assessments will not be included in the by visit summary 
tables, but will be included in subject listings.  
 
18.5 
Missing Date of Investigational Product  
When the date of the last dose of investigational product is missing for a subject in the Safety 
Population, all efforts should be made to obtain the date from the investigator.  If it is still 
missing after all efforts, then the last visit date when investigational product was returned will 
be used in the calculation of treatment duration.   


Protocol SHP640-301 
 
 
 
18.6 
Missing Date Information for Prior or Concomitant Medications  
 
For prior or concomitant medications, including rescue medications, incomplete (ie, partially 
missing) start date and/or stop date will be imputed.  When the start date and the stop date are 
both incomplete for a subject, impute the start date first.     
18.6.1 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields.  If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing day and month 
 
If the year of the incomplete start date is the same as the year of the date of the first dose 
of investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields 
 
If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields 
 
If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
Missing day only 
 
If the month and year of the incomplete start date are the same as the month and year of 
the date of the first dose of investigational product, then the day of the date of the first 
dose of investigational product will be assigned to the missing day 
 
If either the year is before the year of the date of the first dose of investigational product 
or if both years are the same but the month is before the month of the date of the first 
dose of investigational product, then the last day of the month will be assigned to the 
missing day 
 
If either the year is after the year of the date of the first dose of investigational product 
or if both years are the same but the month is after the month of the date of the first 
dose of investigational product, then the first day of the month will be assigned to the 
missing day.  
18.6.2 
Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields.  If the date of the 
last dose of investigational product is missing, then replace it with the last visit date.  If the 
imputed stop date is before the start date (imputed or non-imputed start date), then the 
imputed stop date will be equal to the start date. 


Protocol SHP640-301 
 
 
 
Missing day and month 
 
If the year of the incomplete stop date is the same as the year as of the date of the last 
dose of investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields 
 
If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields 
 
If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
Missing day only 
 
If the month and year of the incomplete stop date are the same as the month and year of 
the date of the last dose of investigational product, then the day of the date of the last 
dose of investigational product will be assigned to the missing day 
 
If either the year is before the year of the date of the last dose of investigational product 
or if both years are the same but the month is before the month of the date of the last 
dose of investigational product, then the last day of the month will be assigned to the 
missing day 
 
If either the year is after the year of the last dose of investigational product or if both 
years are the same but the month is after the month of the date of the last dose of 
investigational product, then the first day of the month will be assigned to the missing 
day. 
 
18.7 
Missing Date Information for Adverse Events  
For AEs, incomplete (i.e. partially missing) start dates will be imputed if the subject is 
missing whether the event occurred prior to the first study drug dose. Incomplete stop dates 
will not be imputed.  
18.7.1 
Incomplete Start Date  
If incomplete state date needs to be imputed, then follow same rules as in Section 18.6.1. 
 
18.8 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned.  If the severity is missing for an AE 
starting after the first dose of investigational product, then a severity of “Severe” will be 
assigned.  The imputed values for severity assessment will be used for incidence summaries. 
while both the actual and imputed values will be used in data listings. 


Protocol SHP640-301 
 
 
 
18.9 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting after the first dose 
of investigational product, a causality of “Related” will be assigned.  The imputed values for 
relationship to double-masked investigational product will be used for incidence summaries, 
while both the actual and imputed values will be presented in data listings. 


Protocol SHP640-301 
 
 
 
19. 
REFERENCES 
 
1. Pocock SJ, Simon R 1975. Sequential treatment assignment with balancing for 
prognostic factors in the controlled clinical trial. Biometrics; 31: 103-15. 


Protocol SHP640-301 
 
 
 
20. 
APPENDIX 
 
20.1 
Example SAS Code for Generating Descriptive Statistics  
*For binary endpoint; 
proc freq data = testData; 
tables binary_endpoint / binomial (exact level='Yes') alpha=0.05; 
by visit treatment; 
run; 
 
 
 


Protocol SHP640-301 
 
 
 
21. 
TABLE OF CONTENTS FOR FIGURES, TABLES, AND 
LISTINGS 
 
Table 
Title 
14.1.1.1 
Subject Disposition (Screened Population) 
14.1.1.2 
Subject Disposition by Age Strata – (Screened Population) 
14.1.2.1.1 
Demographics (Safety Population) 
14.1.2.1.2 
Demographics (ITT Population) 
14.1.2.1.3 
Demographics (mITT Population) 
14.2.1.1 
Clinical Resolution in Study Eye by Visit (mITT Population) 
14.2.1.2 
Adenoviral Eradication in Study Eye as Assessed by CC-IFA by 
Visit (mITT Population) 
14.2.1.3 
At Least 2 Point reduction in Global Clinical Score From Baseline 
in Study Eye by Visit (mITT Population) 
14.2.1.4 
Clinical Resolution in Study Eye by Visit (ITT Population) 
14.3.1.1 
Overall Treatment-emergent Adverse Events by Treatment Group 
(Safety Population) 
14.3.1.2.1 
Ocular Treatment-emergent Adverse Events by System Organ 
Class, Preferred Term and Treatment Group (Safety Population) 
14.3.1.2.2 
Non-Ocular Treatment-emergent Adverse Events by System Organ 
Class, Preferred Term and Treatment Group (Safety Population) 
14.3.1.3.1 
Frequently Occurring (≥5% in Any Treatment Group) Ocular 
Treatment-emergent Adverse Events by Preferred Term and 
Treatment Group (Safety Population) 
14.3.1.3.2 
Frequently Occurring (≥5% in Any Treatment Group) Non-Ocular 
Treatment-emergent Adverse Events by Preferred Term and 
Treatment Group (Safety Population) 
14.3.2.1.1 
Ocular Treatment-emergent Adverse Events with an Outcome of 
Death by System Organ Class, Preferred Term and Treatment 
Group  (Safety Population) 
14.3.2.1.2 
 
Non-Ocular Treatment-emergent Adverse Events with an Outcome 
of Death by System Organ Class, Preferred Term and Treatment 
Group  (Safety Population) 


Protocol SHP640-301 
 
 
 
Table 
Title 
14.3.2.1.3 
 
Ocular Treatment-emergent Serious Adverse Events by System 
Organ Class, Preferred Term and Treatment Group (Safety 
Population) 
 
14.3.2.1.4 
 
Non-Ocular Treatment-emergent Serious Adverse Events by 
System Organ Class, Preferred Term and Treatment Group (Safety 
Population) 
14.3.2.2.1 
Ocular Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group (Safety 
Population) 
14.3.2.2.2 
Non-Ocular Treatment-emergent Adverse Events by Maximum 
Severity, System Organ Class, Preferred Term and Treatment 
Group (Safety Population) 
14.3.2.3.1 
 
Ocular 
Treatment-emergent 
Adverse 
Events 
Leading 
to 
Discontinuation by System Organ Class, Preferred Term and 
Treatment Group (Safety Population) 
14.3.2.3.2 
 
Non-Ocular Treatment-emergent Adverse Events Leading to 
Discontinuation by System Organ Class, Preferred Term and 
Treatment Group (Safety Population) 
14.3.3.1.1 
Ocular Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group (Safety Population) 
14.3.3.1.2 
Non-Ocular Treatment-emergent Adverse Events Considered 
Related to Investigational Product by System Organ Class, 
Preferred Term and Treatment Group (Safety Population) 
14.3.4.1.1 
Ocular Local Tolerability Treatment-emergent Adverse Events by 
System Organ Class, Preferred Term and Treatment Group (Safety 
Population) 
14.3.4.1.2 
Ocular Local Tolerability Treatment-emergent Adverse Events 
Considered Related to Investigational Product by System Organ 
Class, Preferred Term and Treatment Group (Safety Population) 
14.3.4.1.3 
Ocular Local Tolerability Treatment-emergent Adverse Events 
Considered Not Related to Investigational Product by System 
Organ Class, Preferred Term and Treatment Group (Safety 
Population) 
14.3.6.1 
Best Corrected Visual Acuity (LogMar) by Visit (Safety 
Population) 
14.3.6.2 
Slit Lamp Biomicroscopy by Visit (Safety Population) 


Protocol SHP640-301 
 
 
 
Table 
Title 
14.3.6.3 
Dilated/Non-Dilated Fundus Examination by Visit 
(Safety 
Population) 
14.3.6.4 
Red Reflex Examination by Visit (Safety Population – Infants and 
Small Children) 
14.3.8.1 
Duration of Exposure to Investigational Product (Safety Population) 
 
 
 
Listing 
Title 
16.2.1.1 
Screen Failures 
16.2.1.2 
Subjects Disposition (ITT Population) 
16.2.1.3 
Early Termination by Reason (ITT Population) 
16.2.1.4 
Treatment Unmasking (ITT Population) 
16.2.2 
Protocol Deviations (ITT Population) 
16.2.3 
Study Population (ITT Population) 
16.2.4.1 
Demographics (ITT Population) 
16.2.4.2 
Current Conjunctivitis Event (Safety Population) 
16.2.4.3 
Ocular Medical History (Safety Population) 
16.2.4.4 
Non-Ocular Medical History (Safety Population) 
16.2.4.5 
Ocular Medications (Safety Population) 
16.2.4.6 
Non-Ocular Medications (Safety Population) 
16.2.4.7 
Ocular Procedures (Safety Population) 
16.2.4.8 
Non-Ocular Procedures (Safety Population) 
16.2.4.9 
Ocular Therapies (Safety Population) 
16.2.4.10 Non-Ocular Therapies (Safety Population) 


Protocol SHP640-301 
 
 
 
Listing 
Title 
16.2.5.1 
Dispensing and Return of Investigational Product (Safety Population) 
16.2.5.2 
Instillation of Investigational Product (Safety Population) 
16.2.5.3 
Investigational Product Exposure (Safety Population) 
16.2.5.4 
Study Drug Withheld (Safety Population) 
16.2.6.1 
Conjunctival Signs Evaluation, Global Clinical Score and at Least Two Point 
Reduction from Baseline in Global Clinical Score (ITT Population) 
16.2.6.2 
Clinical Resolution Status in Study Eye (ITT Population) 
16.2.6.3 
Adenoviral Eradication Status (ITT Population) 
16.2.6.4 
Adenovirus Viral Titer as Assessed by qPCR in Study Eye (ITT Population) 
16.2.6.5 
Bacterial Culture Results in Study Eye (ITT Population) 
16.2.6.6 
Ocular Discomfort Evaluation (ITT Population) 
16.2.7.1 
Pre-Treatment Adverse Events (Screen Failure Subjects) 
16.2.7.2 
Pre-Treatment Adverse Events (Safety Population) 
16.2.7.3 
Treatment-Emergent Adverse Events (Safety Population) 
16.2.7.4 
Treatment-Emergent Adverse Events with an Outcome of Death (Safety 
Population) 
16.2.7.5 
Serious Treatment-Emergent Adverse Events (Safety Population) 
16.2.7.6 
Treatment-Emergent 
Adverse 
Events 
Leading 
to 
Discontinuation 
of 
Investigational Product (Safety Population) 
16.2.8.1 
Best Corrected Visual Acuity (Safety Population) 
16.2.8.2 
Slit Lamp Examination (Safety Population) 
16.2.8.3 
Fundus Examination (Safety Population) 
16.2.8.4 
Red Reflex Assessment (Safety Population) 
16.2.8.5 
Urine Pregnancy Test (Safety Population) 
16.2.8.6 
Herpes Simplex Virus Results at Visit 1  (Safety Population) 


Protocol SHP640-301 
 
 
 
Listing 
Title 
16.2.8.7 
Chlamydia Trachomatis and Neisseria Gonorrhea Results at Visit 1 (Safety 
Population – Children <2 months) 
 

Prot_003.pdf: 
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
Amendment 1: 28 November 2016
Amendment 2: 15 February 2017
Amendment 3: 13 December 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.




Shire
CONFIDENTIAL
Page 3
SHP640-301 Protocol Amendment 3
SHP640 (FST-100)
13 Dec 2017
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to the Shire Global Pharmacovigilance and Risk Management 
Department. Applicable fax numbers and e-mail address can be found on the form (sent under 
separate cover). A copy of this form must also be sent to the contract research organization 
(CRO)/Shire medical monitor by fax or e-mail using the details below.
Fax: 
Email: 
For protocol- or safety-related issues in the US and North American region, the investigator must 
contact the Shire medical monitor:
Primary telephone number 
Fax: 
Alternate number: 
For protocol- or safety-related issues in regions other than North America, the investigator 
must contact the Quintiles 24/7 Emergency Contact center:
Primary telephone number:
 
Alternate number: 




Shire
CONFIDENTIAL
Page 5
SHP640-301 Protocol Amendment 3
SHP640 (FST-100)
13 Dec 2017
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)


Shire
CONFIDENTIAL
Page 6
SHP640-301 Protocol Amendment 3
SHP640 (FST-100)
13 Dec 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
ABBREVIATIONS .......................................................................................................................11
STUDY SYNOPSIS ......................................................................................................................12
1.
BACKGROUND INFORMATION.......................................................................................21
1.1
Indication and Current Treatment Options...............................................................21
1.2
Product Background and Clinical Information ........................................................21
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................23
2.1
Rationale for the Study.............................................................................................23
2.2
Study Objectives ......................................................................................................23
2.2.1
Primary Objective..................................................................................................23
2.2.2
Key Secondary Objectives.....................................................................................23
2.2.3
Secondary Objectives.............................................................................................24
2.2.4
Exploratory Objectives ..........................................................................................24
3.
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ..................................................................................25
3.2
Duration and Study Completion Definition .............................................................26
3.3
Sites and Regions .....................................................................................................26
4.
STUDY POPULATION.........................................................................................................27
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................28
4.3
Reproductive Potential .............................................................................................29
4.3.1
Female Contraception............................................................................................29
4.4
Discontinuation of Subjects .....................................................................................30
4.4.1
Reasons for Discontinuation..................................................................................31
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................31
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
5.1
Prior Treatment ........................................................................................................32
5.2
Concomitant Treatment............................................................................................32
5.2.1
Permitted Treatment...............................................................................................32
5.2.2
Prohibited Treatment .............................................................................................32


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6.
INVESTIGATIONAL PRODUCT ........................................................................................34
6.1
Identity of Investigational Product...........................................................................34
6.1.1
Masking the Treatment Assignment ......................................................................34
6.1.2
Commercially Obtained Investigational Product...................................................34
6.2
Administration of Investigational Product(s)...........................................................34
6.2.1
Interactive Response Technology for Investigational Product Management ........34
6.2.2
Allocation of Subjects to Treatment ......................................................................34
6.2.3
Dosing....................................................................................................................35
6.2.4
Unmasking the Treatment Assignment..................................................................35
6.3
Labeling, Packaging, Storage, and Handling ...........................................................35
6.3.1
Labeling .................................................................................................................35
6.3.2
Packaging...............................................................................................................36
6.3.3
Storage ...................................................................................................................36
6.3.4
Special Handling....................................................................................................37
6.4
Drug Accountability.................................................................................................37
6.5
Subject Compliance..................................................................................................38
7.
STUDY PROCEDURES........................................................................................................39
7.1
Study Schedule.........................................................................................................39
7.1.1
Visit 1 (Day 1) .......................................................................................................39
7.1.2
Visit 2 (Day 3), Visit 3 (Day 6), and Visit 4 (Day 8) ............................................41
7.1.3
Visit 5 (End of Study or Early Termination) .........................................................41
7.1.4
Additional Care of Subjects after the Study ..........................................................41
7.2
Study Evaluations and Procedures ...........................................................................41
7.2.1
Demographic and Other Baseline Characteristics .................................................41
7.2.2
Efficacy..................................................................................................................42
7.2.3
Safety .....................................................................................................................42
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................46
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................46
8.1.1
Severity Categorization..........................................................................................46
8.1.2
Relationship Categorization...................................................................................47
8.1.3
Outcome Categorization ........................................................................................47
8.1.4
Symptoms of the Disease Under Study .................................................................47
8.1.5
Pregnancy...............................................................................................................48
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................48
8.2
Serious Adverse Event Procedures ..........................................................................49
8.2.1
Reference Safety Information................................................................................49
8.2.2
Reporting Procedures.............................................................................................49


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8.2.3
Serious Adverse Event Definition .........................................................................50
8.2.4
Serious Adverse Event Collection Time Frame.....................................................50
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................50
8.2.6
Fatal Outcome........................................................................................................51
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................51
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................52
9.1
Data Collection.........................................................................................................52
9.2
Clinical Data Management.......................................................................................52
9.3
Data Handling Considerations..................................................................................52
9.4
Statistical Analysis Process......................................................................................52
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......53
9.6
Sample Size Calculation and Power Considerations................................................53
9.7
Study Population ......................................................................................................53
9.8
Efficacy Analyses.....................................................................................................54
9.8.1
Study Eye Designation...........................................................................................54
9.8.2
Primary Efficacy Endpoint ....................................................................................54
9.8.3
Key Secondary Efficacy Endpoints .......................................................................55
9.8.4
Secondary Efficacy Endpoints...............................................................................56
9.8.5
Exploratory Efficacy Endpoints.............................................................................57
9.9
Safety Analyses........................................................................................................57
9.10
Other Analyses .........................................................................................................58
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................59
10.1
Sponsor’s Responsibilities .......................................................................................59
10.1.1 Good Clinical Practice Compliance.......................................................................59
10.1.2 Indemnity/Liability and Insurance.........................................................................59
10.1.3 Public Posting of Study Information......................................................................59
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................60
10.1.5 Study Suspension, Termination, and Completion..................................................60
10.2
Investigator’s Responsibilities .................................................................................60
10.2.1 Good Clinical Practice Compliance.......................................................................60
10.2.2 Protocol Adherence and Investigator Agreement..................................................61
10.2.3 Documentation and Retention of Records.............................................................61
10.3
Ethical Considerations..............................................................................................62
10.3.1 Informed Consent...................................................................................................62
10.3.2 Institutional Review Board or Ethics Committee..................................................63
10.4
Privacy and Confidentiality......................................................................................64


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10.5
Study Results/Publication Policy .............................................................................64
11. REFERENCES .......................................................................................................................66
12. APPENDICES ........................................................................................................................68
Appendix 1
Protocol History .....................................................................................69
Appendix 2
Scales and Assessments .........................................................................70


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LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................19
Table 2
Common Excluded Treatments and Associated Washout Periods................33
LIST OF FIGURES
Figure 1
SHP640-301 Study Design............................................................................25


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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
HSV
Herpes Simplex Virus
ICH
International Conference on Harmonisation
IOP
intraocular pressure
IRB
Institutional Review Board
IRT
interactive response technology
ITT
Intent to Treat
mITT
Modified Intent to Treat
MRSA
methicillin-resistant Staphylococcus aureus
PVP-I
povidone-iodine
qPCR
quantitative polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment- emergent adverse event
US
United States


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STUDY SYNOPSIS
Protocol number: SHP640-301
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 100 sites across North America, South America, Asia/Pacific,
Europe, the Middle East and Africa.
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]) 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:

Adenovirus viral titer assessed by quantitative polymerase chain reaction (qPCR) at Visit 
3 (Day 6) and 4 (Day 8)

Adenoviral eradication as assessed by CC-IFA at Visits 4 (Day 8) and 5 (Day 12)

Clinical resolution  of adenoviral conjunctivitis at Visits 2 (Day 3), 4 (Day 8) and 
5 (Day 12) 

Individual clinical signs (bulbar conjunctival injection and watery conjunctival discharge) 
at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)


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
The global clinical score (sum of bulbar conjunctival injection and watery conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 
3 (Day 6), 4 (Day 8) and 5 (Day 12). 

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)

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)

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 
4 (Day 8), and 5 (Day 12) 

To assess the status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected eye at 
baseline

To evaluate the safety and tolerability of SHP640 compared to 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 investigational product in each eye 4 times daily (with a minimum of 2 hours 
between doses) for 7 days.
Methodology:
Once screening and baseline assessments are complete and subjects are confirmed eligible to enroll in the study, 
subjects will be randomized, and investigational product will be administered on the same day (Day 1). The first 
dose will be administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 
4 times a day (QID) for 7 days. Additional visits will occur on Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), 
and Visit 5 (Day 12). The study will last up to 13 days. 
Inclusion and exclusion criteria: 
Inclusion Criteria:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions (by 
the parent(s), guardian, or legally authorized representative, if applicable).
2.
Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), guardian, or 
legally authorized representative(s) informed consent (and assent, if applicable) to participate in the 
study.
3.
Subjects of any age at Visit 1 (Note: subjects <3 months of age at Visit 1 must have been full-term, ie 
≥37 weeks gestational age at birth).


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4.
Have a positive AdenoPlus® test at Visit 1 in at least 1 eye.
5.
Have a clinical diagnosis of suspected adenoviral conjunctivitis in at least 1 eye (the same eye as the 
AdenoPlus positive eye) confirmed by the presence of the following minimal clinical signs and 
symptoms in that same eye:

Report presence of signs and/or symptoms of adenoviral conjunctivitis for ≤ 4 days prior to Visit 1

Bulbar conjunctival injection: a grade of ≥1 (mild) on a 0-4 Bulbar Conjunctival Injection Scale.

Watery conjunctival discharge: a grade of ≥1 (mild) on a 0-3 Watery Conjunctival Discharge Scale
6.
Be willing to discontinue contact lens wear for the duration of the study.
7.
Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as measured using 
an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will be assessed by an age 
appropriate method in accordance with the AAP Policy Statement for Visual System Assessment in 
Infants, Children, and Young Adults by Pediatricians (Donahue and Baker 2016; American Academy 
of Pediatrics 2016). The policy statement recommends formal vision screening can begin at 3 years of 
age. VA measurements for children under the age of 3 will be done at the discretion of the investigator. 
If not done, child should be able to fixate on and follow a moving object, except subjects <2 months of 
age who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion of the 
investigator. 
8.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of non-childbearing potential. 
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1.
Current or recurrent disease that could affect the action, absorption, or disposition of the investigational 
product, or clinical or laboratory assessments, per investigator’s discretion.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may make the 
subject unlikely to fully complete the study, or any condition that presents undue risk from the 
investigational product or procedures.
3.
Have known or suspected intolerance or hypersensitivity to the investigational product, closely related 
compounds, or any of the stated ingredients. 
4.
Prior enrollment in a FST-100 or SHP640 clinical study.
5.
Subjects who are employees, or immediate family members of employees (who are directly related to 
study conduct), at the investigational site.
6.
Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned for the 
period of the study.
7.
Have a preplanned overnight hospitalization during the period of the study.
8.
Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, iritis, 
ulcerative keratitis, chronic blepharoconjunctivitis), other than adenoviral conjunctivitis.
9.
Have presence of corneal subepithelial infiltrates at Visit 1.
10. Have active or history of ocular herpes.
11. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with the 
diagnosis of non-infectious conjunctivitis (except presumed seasonal/perennial allergic conjunctivitis), 
or non-adenoviral ocular infection (eg, bacterial, fungal, acanthamoebal, or other parasitic). Note: 
history or concomitant presence of presumed seasonal or perennial allergic conjunctivitis 
signs/symptoms is not exclusionary.
12. Neonates or infants (ie, subjects less than 12 months of age) who have suspected or confirmed (based 
on the result of any test conducted prior to screening) conjunctivitis of gonococcal, chlamydial, 
herpetic or chemical origin.
13. Neonates or infants (ie, subjects less than 12 months of age) whose birth mothers had any sexually 
transmitted disease within 1 month of delivery or any history of genital herpes.


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14. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
15. Presence of any significant ophthalmic condition (eg, Retinopathy of Prematurity, congenital cataract, 
congenital glaucoma) or other congenital disorder with ophthalmic involvement that could affect study 
variables.
16. Be a known intraocular pressure (IOP) steroid responder, have a known history or current diagnosis of 
glaucoma, or be a glaucoma suspect.
17. Have any known clinically significant optic nerve defects. 
18. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to previous 
corneal trauma or dry eye syndrome; presence of corneal epithelial defect or any significant corneal 
opacity at Visit 1.
19. Presence of significant, active condition in the posterior segment which requires invasive treatment (eg, 
intravitreal treatment with VEGF inhibitors or corticosteroids) and may progress during the study 
participation period.
20. Have used any topical ocular or systemic anti-virals or antibiotics within ≤7 days of enrollment. 
21. Have used any topical ocular NSAIDs within ≤1 day of enrollment.
22. Have used any topical ophthalmic steroids in the last ≤14 days.
23. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 days 
prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no anticipated change in 
dose for the duration of the study. Topical dermal steroids are allowed except in the peri-ocular area.
24. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
25. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all topical 
ophthalmic products for the duration of the study. Use of hot or cold compresses is also not permitted 
during the study.  
26. Have any significant ocular disease (eg, Sjogren's syndrome) or any uncontrolled systemic disease or 
debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted diseases/infections, 
diabetes or cystic fibrosis), that may affect the study parameters, per the investigator’s discretion.
27. Any known history of immunodeficiency disorder or known active conditions predisposing to 
immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of  active 
hepatitis A (antihepatitis A virus immunoglobulin M), or organ or bone marrow transplantation.
28. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study.
Maximum duration of subject involvement in the study:
Subject participation will last up to 13 days.
Screening, randomization and the first treatment administration will occur at Visit 1 (Day 1). 
Additional visits will occur on Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), and Visit 5 (Day 12). 
All follow-up procedures will be conducted at Visit 5 (Day 12).
Endpoints and statistical analysis:
Primary Efficacy Endpoint:
Clinical resolution status (defined as absence of bulbar conjunctival injection and watery conjunctival 
discharge) in the study eye at Visit 3 (Day 6) between SHP640 and placebo.
Key Secondary Efficacy Endpoints:
Clinical resolution status 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).


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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.
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 signs score (bulbar conjunctival injection and watery conjunctival discharge) 
and change from baseline at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the  study eye

The global clinical score (as defined as the sum of bulbar conjunctival injection and watery 
conjunctival discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 
3 (Day 6), 4 (Day 8) and 5 (Day 12) in the  study eye

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 
3 (Day 6), 4 (Day 8) and 5 (Day 12) in the  study eye

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with neither injection 
nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the  study 
eye

The status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye at Visits 2 (Day 3), 
3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected eye at baseline

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8), and 
5 (Day 12) in the study eye
Safety Endpoints:

Best Corrected Visual Acuity (BCVA)

Slit Lamp Biomicroscopy 

Non-dilated/ Dilated Fundus Examination

Urine Pregnancy Testing (for females of childbearing potential)

Adverse Events (AEs)
Statistical Methods:
The analyses on primary, key secondary, secondary and exploratory efficacy endpoints will be performed on the 
mITT population (unless specified otherwise) and will be presented by treatment group. Additional sensitivity 
analyses may be conducted on the ITT population. Safety analysis will be conducted on the safety population.


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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 investigational product and have a positive CC-IFA adenovirus test at baseline in the study 
eye.
Designation of Study Eye:
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a score of at least 1 
for both watery conjunctival discharge and bulbar conjunctival redness at baseline (baseline is defined as the 
assessments taken at Visit 1 (Day 1):

For subjects with both eyes eligible and both with a positive CC-IFA result at baseline or both eyes 
eligible and both with a negative CC-IFA result at baseline, the study eye will be the eye with the 
highest global clinical score (sum of the scores for discharge and redness) at baseline. If both eyes have 
the same global clinical score at baseline, then the study eye will be the right eye.

For subjects with both eyes eligible with a positive CC-IFA result in one eye at baseline, the baseline 
CC-IFA positive eye will be the study eye.

For subjects with only one eligible eye, the eligible eye will be the study eye irrespective of its baseline 
CC-IFA status.
Primary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. There is a single 
primary comparison for the single primary endpoint. Therefore, no adjustment of multiplicity is needed for the 
hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 6) will be compared 
between the SHP640 and placebo group. The comparison will be based on the proportion of subjects with 
clinical resolution in the study eye at Visit 3 (Day 6) using Fisher’s Exact test at two sided 0.05 significance 
level. 
If subjects have missing clinical resolution status at Visit 3 (Day 6), then the last post-baseline observation will 
be carried forward (LOCF) for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with clinical resolution in 
the study eye between SHP640 Ophthalmic Solution and Placebo with the alternative of the non-zero difference 
in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with two-sided Fisher’s Exact test at 5% 
level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical method(s) 
including other methods of imputation of missing data. Sensitivity analyses may be conducted in the ITT in 
addition to the mITT.
Key Secondary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. 


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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 number of subjects (n), mean, median, standard deviation, minimum, maximum and 
confidence intervals.  Binary endpoints will be summarized by number of subjects (n), frequencies proportions 
and confidence intervals. Time to event endpoint will be summarized by Kaplan-Meier survival estimates.
Safety Analyses:
Safety data will be presented for the Safety Population by treatment group and overall. Adverse events will be 
coded using the Medical Dictionary for Regulatory Activities. The number of subjects and percentage with a 
treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated overall, by SOC, 
by preferred term, and by treatment group and overall. Treatment-emergent adverse events will be further 
summarized by severity and relationship to investigational product. Adverse events related to investigational 
product, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized and listed. Any AE that 
occurs after the first dose of investigational product instillation will be considered a TEAE.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or non-ocular AE.
BVCA, Slit Lamp Biomicroscopy, non-dilated/dilated fundus exam, and urine pregnancy test (for females of 
childbearing potential) will be descriptively summarized by treatment group and overall at each applicable visit.


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Study Schedule
Table 1
Schedule of Assessments
Procedure
(All ocular assessments and 
procedures performed bilaterally)
Visit 1
Screeninga & 
Baseline
(Day 1)
-1 Day
Visit 2
(Day 3)
+1 Day
Visit 3
(Day 6)
Visit 4 
(Day 8)
+1 Day
Visit 5b
(Day 12)
+2 Days
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
Ocular Discomfort Scale
X
X
X
X
X
Best corrected visual acuity
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
Bulbar conjunctival injection 
evaluation
X
X
X
X
X
Watery conjunctival discharge 
evaluation
X
X
X
X
X
AdenoPlus®  test
Xd
Conjunctival swab for viral culturee
Xm
Xf
Xf
Xf
Xf
Conjunctival swab for bacterial 
cultureg
X
Xf,g
Xf
Non-dilated/ dilated fundus 
examinationh
X
X
Randomizationi
X
Dispense investigational product j
X
Instill investigational product
Xj
Xk
Xk
Collect investigational product
X
Xb
Compliance assessment
X
X
X
Xb
Drug accountability
X
Xb


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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)
+1 Day
Visit 3
(Day 6)
Visit 4 
(Day 8)
+1 Day
Visit 5b
(Day 12)
+2 Days
Adverse events
Xl
X
X
X
X
Study completion
X
CC-IFA= cell culture-immunofluorescence assay; HSV= herpes simplex virus; qPCR= quantitative polymerase 
chain reaction; 
a Informed consent and confirmation of inclusion/exclusion criteria can be conducted on Day -1; Inclusion/Exclusion 
must be re-confirmed on Day 1.
b If investigational product is discontinued, regardless of the reason, all discontinued subjects should proceed to 
Visit 5 whenever possible. Subjects that discontinue the study and proceed to Visit 5 should perform all Visit 5 
assessments as well as drug return, compliance and accountability.
c Women of childbearing potential, prior to enrollment and at exit from the study.
d If not previously conducted within 24 hours of Visit 1 (Day 1)
e One swab sample from inferior conjunctival cul-de-sac of each eye will be collected for all viral testing. If the 
CC-IFA test is positive, qPCR will be performed. Adenoviral serotyping will be conducted at baseline only.
f Conjunctival swab samples MUST be taken at least 12 hours after the last dose of investigational product at 
Visits 2, 3, 4 and ET, if applicable.
g One swab sample from each conjunctival cul-de-sac will be collected for all bacterial testing.
h If a non-dilated fundus exam is not feasible, a dilated examination should be conducted. For each subject, the exam 
should be conducted the same way (either non-dilated or dilated) at both Visit 1 and Visit 5 (or ET).    
i All assessments, randomization, and investigational product instillation on Day 1 must take place with sufficient 
time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses)
j The investigational product bottle should be shaken well prior to use at each dosing. The first dose will be 
administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a day for 
7 days.
k Investigational product instillation should only be performed in-office if it is necessary.
l Monitoring for adverse events will begin after informed consent is obtained.
m This sample will be used for baseline HSV testing for all subjects. For subjects <2 months of age, testing will also 
be conducted using the same sample for chlamydia and gonorrhea detection.


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Conjunctivitis affects all populations worldwide of all ages and social strata, irrespective of 
gender. Within infectious conjunctivitis, viral etiology may account for up to 80% of all cases 
in adults and bacterial conjunctivitis is the second most common cause of infectious 
conjunctivitis overall. Infectious conjunctivitis represents a serious public health issue due 
to a risk of highly infectious epidemics, lost productivity, significant patient discomfort, and 
in some cases permanent visual compromise from long-term, immune-mediated sequelae (Ford 
et al., 1987; Nauheim et al., 1990; Gordon et al., 1993; Pelletier et al., 2009; Capriotti et al., 
2010).
Adenoviruses, unlike bacteria, are not part of the normal flora of the ocular surface and their 
presence is indicative of an infection (Cambon and Pollard, 1959; Willamson et al., 1975; 
Vastine et al., 1977; Gigliotti et al., 1981; Kaneko et al., 2008). It is the most reported cause of 
viral conjunctivitis in up to 75% of cases (Wilkins et al., 2011). Adenoviral conjunctivitis is 
typically spread through direct contact between the eye and hands that are contaminated with the 
virus via contact with infected eye discharge, fecal matter, or respiratory discharge (CDC, 2010). 
Given the highly transmittable nature of the disease, it is not surprising that it is observed to be 
most prevalent in densely populated, overcrowded areas, or in the presence of poor hygiene, or 
both (Capriotti et al., 2010).
Adenoviral conjunctivitis typically lasts 14-21 days (Wilkins et al., 2011). The onset is usually 
rapid and the infection often spreads from one eye to the other (AAO Cornea/External Disease 
PPP Panel, 2013). 
Currently, there are no approved treatments for adenoviral conjunctivitis; therapeutic options are 
limited to supportive therapies and palliative measures such as cold compresses, artificial tears, 
and topical antihistamines (AAO Cornea/External Disease PPP Panel, 2013). This Phase 3 study 
is being conducted to evaluate the clinical efficacy and safety of SHP640 for the treatment of 
adenoviral conjunctivitis.
1.2
Product Background and Clinical Information
SHP640, a novel topical ophthalmic suspension, is currently under development for the treatment 
of infectious conjunctivitis (adenoviral and bacterial).
SHP640 contains 2 active ingredients: povidone-iodine (PVP-I) and dexamethasone. PVP-I is 
a multivalent broad-spectrum local antiseptic with bactericidal and fungicidal properties. The 
effect on vegetative cells of various bacteria and fungi is due to the liberation of free iodine 
from the complex. It is effective against many viruses, protozoa, yeasts, cysts, and spores 
(Betadine, 2004). Dexamethasone is a corticosteroid routinely used as a topical ophthalmic 
suspension for the treatment of ocular inflammation. It suppresses the inflammatory response to 
a variety of causes of inflammation (Maxidex, 2007). Both components are currently 
approved for use in other indications (at similar or higher concentrations) and have been shown 
to be safe and efficacious for use on the ocular surface in humans. 


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The combination of PVP-I and dexamethasone has been shown to rapidly kill common ocular 
pathogens, including viruses, gram-positive bacteria (including MRSA), and gram-negative 
bacteria (Pelletier et al., 2011).
Always refer to the latest version of the SHP640 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy and safety of SHP640. 


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The clinical presentation of conjunctivitis is often nonspecific and differential diagnosis of 
different types of conjunctivitis can be challenging (Azari and Barney, 2013; O'Brien et al., 
2009). Diagnostic testing to differentiate the underlying cause of infection is rarely performed 
in a clinical setting; misdiagnosis can occur in up to 50% of cases, which often results in 
improper antibiotic treatment (Visscher et al., 2009). Incorrect treatment can not only increase 
healthcare costs from unnecessary antibiotic prescriptions and repeat office visits, but can also 
pose serious risks for people with certain viral and bacterial variants (eg, herpes simplex or 
methicillin-resistant Staphylococcus aureus [MRSA]). In addition, there is also a risk of overuse 
and misuse of antibiotics, which are ineffective in the treatment of viral infections (Statham et 
al., 2008). Currently there is no approved medication for the treatment of adenoviral 
conjunctivitis. An unmet medical need therefore exists for a safe and efficacious treatment that 
addresses both bacterial and adenoviral conjunctivitis, two of the leading causes of acute 
infectious conjunctivitis.
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, 
with dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious 
and inflammatory components of adenoviral and bacterial conjunctivitis.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical 
resolution (defined as absence of bulbar conjunctival injection and watery conjunctival 
discharge) compared with placebo in the treatment of subjects with adenoviral conjunctivitis in 
the study eye at Visit 3 (Day 6). 
2.2.2
Key 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]) 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).


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Adenoviral eradication is defined in Section 7.2.2.
2.2.3
Secondary Objectives
Secondary objectives of this study are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints:

Adenovirus viral titer assessed by quantitative polymerase chain reaction (qPCR) at 
Visit 3 (Day 6) and 4 (Day 8)

Adenoviral eradication as assessed by CC-IFA at Visits 4 (Day 8) and 5 (Day 12)

Clinical resolution of adenoviral conjunctivitis at Visits 2 (Day 3), 4 (Day 8) and 5 
(Day 12)

Individual clinical signs (bulbar conjunctival injection and watery conjunctival 
discharge) at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)

The global clinical score (sum of bulbar conjunctival injection and watery conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 6), 4 (Day 8) and 5 (Day 12). 

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)

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)

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 
(Day 8), and 5 (Day 12) 

To assess the status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye
at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected eye at 
baseline

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the 
treatment of subjects with adenoviral conjunctivitis
2.2.4
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 will be randomized into the study at Visit 1 (Day 1). Subjects will 
be randomized 2:2:1 to receive either SHP640, PVP-I, or placebo within each stratum. 
Randomization will be stratified by age to maintain the randomization ratio among subjects 
< 6 years, 6 to <18 years and subjects ≥18 years.
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced randomization will be used in this study to 
maintain the randomization ratio within each stratum. 
Once screening and baseline assessments are complete and subjects are confirmed eligible to 
enroll in the study, subjects will be randomized, and investigational product will be administered 
on the same day (Day 1). The first dose will be administered by site staff on Day 1, and 
thereafter subjects will administer 1 drop in each eye 4 times a day (QID) for 7 days. Additional 
visits will occur on Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), and Visit 5 (Day 12). All 
follow-up procedures will be conducted at Visit 5 (Day 12). The study will last up to 13 days. 
Figure 1 provides the study design.
Figure 1
SHP640-301 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 100 sites across North America, South America, 
Asia/Pacific, Europe, the Middle East, and Africa.


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


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


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


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


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


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


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Table 2  
Common Excluded Treatments and Associated Washout Periods
Minimum Time Prior to First 
Dose
Notes
Treatment
30 
days 
14 
days
7 
days
1 
day
2 
hours
Topical ocular NSAIDs
X
Topical ocular or systemic anti-virals or 
antibiotics
X
Topical ophthalmic steroids
X
Systemic corticosteroid agents
X
Stable use of inhaled or nasal corticosteroids
X
Allowed ≥30 days if no 
anticipated dose changes 
during the study
Non-corticosteroid 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, IMP returns, accountability of 
IMP, and emergency unmasking.
6.2.2
Allocation of Subjects to Treatment 
This is a double-masked, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment is 
automatically assigned by the IRT.
Randomization will be stratified by age to maintain the randomization ratio among subjects 
< 6 years, 6 to <18 years and subjects ≥18 years.  Subjects will be randomly assigned to receive 
SHP640, PVP-I 0.6%, or placebo based on a 2:2:1 ratio [SHP640: PVP-I 0.6%: placebo] within 
the randomization strata.


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


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


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


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


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


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


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7.1.2
Visit 2 (Day 3), Visit 3 (Day 6), and Visit 4 (Day 8)
Visit 2 (Day 3 [+1 day]), Visit 3 (Day 6), and Visit 4 (Day 8 [+1 day]) assessments will be 
performed as outlined in Table 1 and as described in the Study Operations Manual. Assessments 
should be performed in descending order as listed.
Subject compliance will be verified verbally during study visits. In cases of non-compliance the 
investigator should determine if the medical monitor must be contacted for consultation. 
Subjects should not instill investigational product within 12 hours of scheduled Study Visits. To 
ensure this, subjects should be reminded to not dose the morning of Visits 2, 3 and 4. 
Investigational product instillation should only be performed in-office if it is necessary, and 
should be done once all other assessments are completed. Subjects who instill investigational 
product less than 12 hours before study visits will be recorded as protocol deviations.
7.1.3
Visit 5 (End of Study or Early Termination)
Safety follow-up will be conducted at Visit 5 (the end of study visit). Visit 5 (Day 12 [+2 days]) 
assessments will be performed as outlined in Table 1. Assessments should be performed in 
descending order as listed.
Subjects who discontinue the study and proceed to Visit 5 for early termination should have 
investigational product collected, a compliance assessment, and drug accountability assessed at 
their final visit.
All AEs and SAEs that are not resolved at the time of Visit 5 or early termination will be 
followed to closure (see Section 8.1).
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
7.2.1.1
Demographics
Demographic information will be collected at Visit 1. Date of Birth (where permitted), Age, Sex, 
Race, and Ethnicity will be recorded.
7.2.1.2
Medication and Medical History
Medication History
Refer to Section 5 for full details on collection of prior treatment.
The investigator will categorize treatments as ocular (specified as left eye, right eye or both eyes) 
or non-ocular based on the indication for use.  Prior treatment information must be recorded on 
the appropriate CRF page.  


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Medical History
The site must record all clinically or medically relevant information regardless of how much time 
has elapsed since the date of any diagnosis. Medical history will be classified as ocular (specified 
as left eye, right eye or both eyes) or non-ocular by the investigator. History should include, but 
is not limited to: 

History of ocular diseases/conditions. 

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, and any other non-ocular diseases/underlying conditions within 
the past year prior to the Screening Visit (Visit 1).
7.2.1.3
AdenoPlus Test
The AdenoPlus test will be performed at Visit 1 as outlined in Table 1. A positive result in at 
least one eye is required for enrollment in this study.
The AdenoPlus test is an in-office test that allows for the detection of adenoviral antigens 
directly from human eye fluid. A small tear sample is transferred onto the AdenoPlus test, which 
confirms the presence of adenovirus and the viral form of conjunctivitis. 
Please refer to the Study Operations Manual for a detailed description of the AdenoPlus Test and 
administration.
7.2.2
Efficacy
7.2.2.1
Clinical Resolution
Clinical resolution of adenoviral conjunctivitis is defined as the absence (score = 0) of bulbar 
conjunctival injection and watery conjunctival discharge in the study eye. Bulbar Conjunctival 
Injection will be assessed based on a 0-4 scale which uses pictures from the Validated Bulbar 
Redness (VBR) Scale and Watery Conjunctival Discharge will be assessed based on a 0-3 scale. 
Details of the Bulbar Conjunctival Injection and Watery Conjunctival Discharge scales are 
located in the Study Operations Manual.
7.2.2.2
Adenoviral Eradication
Adenoviral eradication for an eye is defined as negative CC-IFA in that eye.  CC-IFA for each 
eye will be conducted using conjunctival swab samples collected at each visit. See the 
Laboratory Manual for further details.
7.2.3
Safety
Safety assessments will be performed in both eyes.
7.2.3.1
Best Corrected Visual Acuity (BCVA)
The BCVA will be performed prior to slit lamp examination during the study as outlined in 
Table 1.


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The complete instructions for performing the BCVA are in the Study Operations Manual. 
Changes in VA will be assessed for clinical significance. Clinically significant changes should be 
recorded in the source and on the eCRF as an AE.
For subjects who are too young to use an ETDRS chart, use an age-appropriate measurement 
method in accordance with the AAP Policy Statement for Visual System Assessment in Infants, 
Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American Academy of 
Pediatrics, 2016; located in the Study Operations Manual). The policy statement recommends 
formal vision screening can begin at 3 years of age. VA measurements for children under the age 
of 3 will be done at the discretion of the investigator. If not done, child should be able to fixate 
on and follow a moving object. This is not a requirement in subjects <2 months of age since the 
ability does not develop until about 2 months of age. However, if an infant <2 months of age is 
able to fix and follow, it should be recorded. The enrollment of subjects <2 months of age will be 
based on subject qualifying all other eligibility criteria and investigator discretion.
VA is to be measured using the same method at all visits in the same subject.
7.2.3.2
Slit Lamp Biomicroscopy
Slit lamp biomicroscopy (or hand held slit lamp) will be performed during the study as outlined 
in Table 1. Magnification of the slit lamp will be consistent with standard clinical practice. The 
subject will be seated.
Observations will be graded as Normal or Abnormal. Abnormal findings will be described, and 
clinically significant abnormalities should be recorded in the source and on the electronic CRF 
(eCRF) (in Medical History at Screening; any changes from the screening visit may be recorded 
as adverse events by the investigator). Please note the investigator may use his/her discretion to 
determine whether Not Clinically Significant (NCS) and disease progression should be 
considered AEs). The following will be examined at each visit: 

Lids 

Conjunctiva 

Cornea

Anterior Chamber

Iris

Lens
For infants and young children, if the above exams cannot be performed with a slit lamp or a 
hand held slit lamp, an external examination is to be conducted in accordance with American 
Academy of Pediatrics (AAP) Policy Statement for Visual System Assessment in Infants, 
Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American Academy of 
Pediatrics, 2016; located in the Study Operations Manual). The examination of lens in these 
subjects should be conducted at Visit 1 and Visit 5 (or ET visit) and graded based on the external 
examination and red reflex exam (Section 7.2.3.3). 


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All other structures listed above will be examined and graded at all visits based on the external 
examination. Observations will be graded as Normal or Abnormal. Abnormal findings will be 
described.
7.2.3.3
Non-dilated/ Dilated Fundus Examination
Fundus examination must be conducted after BCVA, Slit Lamp Biomicroscopy and conjunctival 
swab for adenoviral and bacterial culture has been collected. 
A non-dilated fundus examination will be performed in all subjects with the exception of infants 
and uncooperative small children during the study as outlined in Table 1.
Observations will be graded as Normal or Abnormal. Abnormal findings will be described.
The following will be examined:

Vitreous

Optic Nerve

Macula
Clinically significant changes should be recorded in the source and on the eCRF as an AE.
If a non-dilated fundus exam is attempted and is not feasible, dilated fundus exam should be 
conducted. The test should be conducted the same way (either dilated or non-dilated) at both 
Visit 1 and Visit 5 (or ET).
For infants and small children in whom a fundus examination cannot be done, a red reflex exam 
will be conducted in accordance with AAP Policy Statement for Visual System Assessment in 
Infants, Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American 
Academy of Pediatrics, 2016; located in the Study Operations Manual). Observations will be 
graded as Normal or Abnormal. Abnormal findings will be described. The red reflex should be 
normal (present and symmetrical for both eyes) at the screening/ baseline visit. 
7.2.3.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.) Any AE that occurs after the first dose of 
investigational product instillation will be considered a TEAE.
Adverse events may also be determined by the investigator during study examinations as 
mentioned in previous sections.
7.2.3.5
Microbiology Laboratory Evaluations
All laboratory assays will be performed according to the laboratory’s normal procedures. 


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All bioanalytical assays for the study will be validated following FDA/ICH guidelines, based on 
the method's intended use. The lab will only receive sample ID numbers and collection dates, the 
lab results will then be transferred to the central lab for data analysis. The lab will not receive 
any information on subject treatment assignment.
The following laboratory assessments will be performed: 

Cell Culture 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.

qPCR: This test will be performed on samples for qualitative detection of HSV at baseline 
(Visit 1). 
One swab sample from each eye will be taken from inferior conjunctival cul-de-sac at all study 
visits for adenoviral testing. For neonates and infants <2 months of age, PCR testing for
qualitative detection of chlamydia and gonorrhea at baseline will also be conducted using the 
baseline visit sample.
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 three items: pain, itching, and 
foreign body sensation. All items will be evaluated using a 0-10 scale. A separate scale will be 
administered for children less than 8 years of age (binary ocular discomfort). Please see the 
Study Operations Manual for a detailed description of this assessment.


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


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


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


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


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


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


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


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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. 
The assumed proportions of subjects with clinical resolution in the 3 treatment arms are based on 
response rates observed in FST100-AVC-004 with a dropout rate of approximately 6% prior to 
Visit 3 in FST100-AVC-004 mITT population which excluded subjects with no post baseline 
data. The dropout rate would become approximately 8% if FST100-AVC-004 mITT population 
included subjects with no post baseline data.
All efficacy analyses will be based on the mITT population with post-baseline LOCF for the 
subjects with missing clinical resolution status at Visit 3 (Day 6).  To ensure 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. 


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The Modified Intent to Treat (mITT) population consists of a subset of the ITT population 
who receive at least one dose of investigational product and have a positive CC-IFA adenovirus 
test at baseline in the study eye.
9.8
Efficacy Analyses
The analyses on primary, key secondary, secondary and exploratory efficacy endpoints will be 
performed on the mITT population (unless specified otherwise) and will be presented by 
treatment group. 
Additional sensitivity analyses may be conducted in the ITT population.
Efficacy data collected at Baseline (Visit 1 [Day 1]) will be used as the baseline for both efficacy 
and safety analyses. For both efficacy and safety analyses, baseline is defined as the assessments 
taken at Visit 1 (Day 1).
9.8.1
Study Eye Designation
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a 
score of at least 1 for both watery conjunctival discharge and bulbar conjunctival redness at 
baseline (baseline is defined as the assessments taken at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive CC-IFA result at baseline or 
both eyes eligible and both with a negative CC-IFA result at baseline, the study eye will be 
the eye with the highest global clinical score (sum of the scores for discharge and redness) at 
baseline. If both eyes have the same global clinical score at baseline, then the study eye will 
be the right eye. 

For subjects with both eyes eligible with a positive CC-IFA result in one eye at baseline, the 
baseline CC-IFA positive eye will be the study eye. 

For subjects with only one eligible eye, the eligible eye will be the study eye irrespective of 
its baseline CC-IFA status.
9.8.2
Primary Efficacy Endpoint
The primary efficacy endpoint is clinical resolution status (defined as absence [ie a score of 0] of 
bulbar conjunctival injection and watery conjunctival discharge) in the study eye at Visit 3 
(Day 6) between SHP640 and placebo.
All efficacy analyses will be performed on the mITT and presented by treatment groups. There is 
a single primary comparison for the single primary endpoint. Therefore, no adjustment of 
multiplicity is needed for the hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 6) will be 
compared between the SHP640 and placebo group. The comparison will be based on the 
proportion of subjects with clinical resolution in the study eye at Visit 3 (Day 6) using Fisher’s 
Exact test at two sided 0.05 significance level. 


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If subjects have missing clinical resolution status at Visit 3 (Day 6), then the last post-baseline 
observation will be carried forward (LOCF) for the determination of clinical resolution of the 
study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with 
clinical resolution in the study eye between SHP640 Ophthalmic Solution and Placebo with the 
alternative of the non-zero difference in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with two-sided Fisher’s 
Exact test at 5% level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical 
method(s) including other methods of imputation of missing data. Sensitivity analyses may be 
conducted in the ITT in addition to the mITT. In addition, descriptive statistics will be generated 
for the primary efficacy endpoint by treatment within the overall pediatric population (ie birth to 
18 years) and within each pediatric age stratum (birth to <6 years and 6 to <18 years) in mITT. A 
detailed plan for primary analysis including additional sensitivity analyses will be described in 
the Statistical Analysis Plan (SAP).
9.8.3
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints of this study are clinical resolution status 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.


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All efficacy analyses will be performed on the mITT and presented by treatment groups. In order 
to maintain the study-wide Type I error at 5.0%, the primary and key secondary hypotheses will 
be tested sequentially using two-sided Fisher’s exact test according to the following sequence: 
Sensitivity analyses will also be done on key secondary efficacy endpoints using similar methods 
as described above. In addition, descriptive statistics will be generated for the key secondary 
efficacy endpoint by treatment within the overall pediatric population (ie birth to 18 years) and 
within each pediatric age stratum (birth to < 6 years and 6 to <18 years) in mITT. Details on the 
analyses will be described in the Statistical Analysis Plan (SAP).
9.8.4
Secondary Efficacy Endpoints
All secondary efficacy analyses will be performed on the mITT and presented by treatment 
group.  No hypothesis testing is planned for the secondary efficacy endpoints.  All secondary 
efficacy endpoint will be summarized by treatment groups using descriptive statistics at each 
assessment visit.  Continuous endpoints will be summarized by number of subjects (n), mean, 
median, standard deviation, minimum, maximum and confidence intervals.  Binary endpoints 
will be summarized by number of subjects (n), frequencies, proportions and confidence intervals. 
Time to event endpoint will be summarized by Kaplan-Meier survival estimates.
Secondary efficacy endpoints are defined as follows:

Absolute and change from baseline in adenovirus viral titer as assessed by qPCR at 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


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
The Individual clinical signs score (bulbar conjunctival injection and watery conjunctival 
discharge) and change from baseline at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)
in the study eye

The global clinical score (defined as the sum of bulbar conjunctival injection and 
watery conjunctival discharge) and change from baseline in the global clinical score 
at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the study eye

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the study eye

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with 
neither injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 6), 
4 (Day 8) and 5 (Day 12) in the study eye

The status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye 
at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 
1 infected eye at baseline

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 
4 (Day 8), and 5 (Day 12) in the study eye
9.8.5
Exploratory Efficacy Endpoints
9.9
Safety Analyses
Safety data will be presented for the Safety Population by treatment group and overall.
Safety data collected at baseline (Visit 1 / Day 1) will be used as the baseline value for safety 
analysis.
Adverse events, including those suggestive of any local tolerability issues, will be coded using 
the Medical Dictionary for Regulatory Activities. The number of subjects and percentage with a 
treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated 
overall, by SOC, by preferred term, and by treatment group and overall. Treatment-emergent 
adverse events will be further summarized by severity and relationship to investigational 
product. Adverse events related to investigational product, AEs leading to withdrawal, SAEs, 
and deaths will be similarly summarized and listed.


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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 and overall 
at each applicable visit:

Best Corrected Visual Acuity (BCVA)

Slit Lamp Biomicroscopy

Lids 

Conjunctiva 

Cornea 

Anterior Chamber 

Iris

Lens 

Non-dilated/ Dilated Fundus Examination

Vitreous 

Optic Nerve 

Macula 

Urine Pregnancy Testing (for females of childbearing potential)
9.10
Other Analyses
No other analyses are planned in this study.


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


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


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


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


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


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


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


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11.
REFERENCES
AAO Cornea/External Disease PPP Panel 2013. American Academy of Ophthalmology (AAO), 
2013 - Cornea/External Disease Preferred Practice Pattern Guidelines. Conjunctivitis. 
San Francisco, CA.
American Academy of Pediatrics 2016. Visual system assessment in infants, children, and young 
adults by pediatricians. Pediatrics, 137, 28-30.
Azari, A. A. & Barney, N. P. 2013. Conjunctivitis: a systematic review of diagnosis and 
treatment. Jama, 310, 1721-9.
Betadine 2004. Betadine Prescribing Information.
Cambon, E. N. & Pollard, M. 1959. Viral studies of the normal eye. Arch Ophthalmol, 62, 562-5.
Capriotti, J. A., Stewart, K. P. & Pelletier, J. 2010. The unique challenges of viral conjunctivitis -
Its similarities to bacterial infection belie key differences that impact clinical care 
[Online]. Ophthalmology Management. Available: 
http://www.ophthalmologymanagement.com/articleviewer.aspx?articleid=104651.
CDC. 2010. Conjunctivitis (pink eye) [Online]. Centers for Disease Control and Prevention. 
Available: http://www.cdc.gov/conjunctivitis/clinical.html.
Donahue, S. P. & Baker, C. N. 2016. Procedures for the Evaluation of the Visual System by 
Pediatricians. Pediatrics, 137.
Ford, E., Nelson, K. E. & Warren, D. 1987. Epidemiology of epidemic keratoconjunctivitis. 
Epidemiol Rev, 9, 244-61.
Gigliotti, F., Williams, W. T., Hayden, F. G., Hendley, J. O., Benjamin, J., Dickens, M., 
Gleason, C., Perriello, V. A. & Wood, J. 1981. Etiology of acute conjunctivitis in 
children. J Pediatr, 98, 531-6.
Gordon, Y. J., Gordon, R. Y., Romanowski, E. & Araullo-Cruz, T. P. 1993. Prolonged recovery 
of desiccated adenoviral serotypes 5, 8, and 19 from plastic and metal surfaces in vitro. 
Ophthalmology, 100, 1835-9; discussion 1839-40.
Kaneko, H., Maruko, I., Iida, T., Ohguchi, T., Aoki, K., Ohno, S. & Suzutani, T. 2008. The 
possibility of human adenovirus detection from the conjunctiva in asymptomatic cases 
during nosocomial infection. Cornea, 27, 527-30.
Maxidex 2007. Maxidex Prescribing Information.
Nauheim, R. C., Romanowski, E. G., Araullo-Cruz, T., Kowalski, R. P., Turgeon, P. W., Stopak, 
S. S. & Gordon, Y. J. 1990. Prolonged recoverability of desiccated adenovirus type 19 
from various surfaces. Ophthalmology, 97, 1450-3.
O'Brien, T. P., Jeng, B. H., McDonald, M. & Raizman, M. B. 2009. Acute conjunctivitis: truth 
and misconceptions. Curr Med Res Opin, 25, 1953-61.
Pelletier, J. S., Miller, D., Liang, B. & Capriotti, J. A. 2011. In vitro efficacy of a povidone-
iodine 0.4% and dexamethasone 0.1% suspension against ocular pathogens. J Cataract 
Refract Surg, 37, 763-6.
Pelletier, J. S., Stewart, K., Trattler, W., Ritterband, D. C., Braverman, S., Samson, C. M., Liang, 
B. & Capriotti, J. A. 2009. A combination povidone-iodine 0.4%/dexamethasone 0.1% 
ophthalmic suspension in the treatment of adenoviral conjunctivitis. Adv Ther, 26, 776-
83.
Pocock, S. J. & Simon, R. 1975. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 31, 103-15.


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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).

Prot_002.pdf: 
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
Amendment 1: 28 November 2016
Amendment 2: 15 February 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.






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


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
TABLE OF CONTENTS.................................................................................................................5
LIST OF TABLES...........................................................................................................................9
LIST OF FIGURES .........................................................................................................................9
LIST OF APPENDICES..................................................................................................................9
ABBREVIATIONS .......................................................................................................................10
STUDY SYNOPSIS ......................................................................................................................11
1.
BACKGROUND INFORMATION.......................................................................................20
1.1
Indication and Current Treatment Options...............................................................20
1.2
Product Background and Clinical Information ........................................................20
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................21
2.1
Rationale for the Study.............................................................................................21
2.2
Study Objectives ......................................................................................................21
2.2.1
Primary Objective..................................................................................................21
2.2.2
Key Secondary Objectives.....................................................................................21
2.2.3
Secondary Objectives.............................................................................................22
2.2.4
Exploratory Objectives ..........................................................................................23
3.
STUDY DESIGN ...................................................................................................................23
3.1
Study Design and Flow Chart ..................................................................................23
3.2
Duration and Study Completion Definition .............................................................24
3.3
Sites and Regions .....................................................................................................24
4.
STUDY POPULATION.........................................................................................................24
4.1
Inclusion Criteria......................................................................................................24
4.2
Exclusion Criteria.....................................................................................................25
4.3
Reproductive Potential .............................................................................................27
4.3.1
Female Contraception............................................................................................27
4.4
Discontinuation of Subjects .....................................................................................28
4.4.1
Reasons for Discontinuation..................................................................................29
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................29
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................29
5.1
Prior Treatment ........................................................................................................29
5.2
Concomitant Treatment............................................................................................30
5.2.1
Permitted Treatment...............................................................................................30
5.2.2
Prohibited Treatment .............................................................................................30


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6.
INVESTIGATIONAL PRODUCT ........................................................................................31
6.1
Identity of Investigational Product...........................................................................31
6.1.1
Masking the Treatment Assignment ......................................................................31
6.1.2
Commercially Obtained Investigational Product...................................................31
6.2
Administration of Investigational Product(s)...........................................................31
6.2.1
Interactive Response Technology for Investigational Product Management ........31
6.2.2
Allocation of Subjects to Treatment ......................................................................31
6.2.3
Dosing....................................................................................................................32
6.2.4
Unmasking the Treatment Assignment..................................................................32
6.3
Labeling, Packaging, Storage, and Handling ...........................................................32
6.3.1
Labeling .................................................................................................................32
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........................................................................................................35
7.1
Study Schedule.........................................................................................................35
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) .........................................................37
7.1.4
Additional Care of Subjects after the Study ..........................................................38
7.2
Study Evaluations and Procedures ...........................................................................38
7.2.1
Demographic and Other Baseline Characteristics .................................................38
7.2.1.1
Demographics.........................................................................................38
7.2.1.2
Medication and Medical History............................................................38
7.2.1.3
AdenoPlus Test ......................................................................................38
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
Best Corrected Visual Acuity (BCVA)..................................................39
7.2.3.2
Slit Lamp Biomicroscopy.......................................................................40
7.2.3.3
Non-dilated/ Dilated Fundus Examination.............................................40
7.2.3.4
Adverse Event Collection.......................................................................41
7.2.3.5
Microbiology Laboratory Evaluations ...................................................41
7.2.3.6
Pregnancy Test .......................................................................................42
7.2.3.7
Health-related Quality of Life Assessments...........................................42


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................42
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................42
8.1.1
Severity Categorization..........................................................................................43
8.1.2
Relationship Categorization...................................................................................43
8.1.3
Outcome Categorization ........................................................................................44
8.1.4
Symptoms of the Disease Under Study .................................................................44
8.1.5
Pregnancy...............................................................................................................44
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................45
8.2
Serious Adverse Event Procedures ..........................................................................46
8.2.1
Reference Safety Information................................................................................46
8.2.2
Reporting Procedures.............................................................................................46
8.2.3
Serious Adverse Event Definition .........................................................................46
8.2.4
Serious Adverse Event Collection Time Frame.....................................................47
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................47
8.2.6
Fatal Outcome........................................................................................................47
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................47
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................48
9.1
Data Collection.........................................................................................................48
9.2
Clinical Data Management.......................................................................................48
9.3
Data Handling Considerations..................................................................................48
9.4
Statistical Analysis Process......................................................................................48
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......49
9.6
Sample Size Calculation and Power Considerations................................................49
9.7
Study Population ......................................................................................................50
9.8
Efficacy Analyses.....................................................................................................50
9.8.1
Study Eye Designation...........................................................................................50
9.8.2
Primary Efficacy Endpoint ....................................................................................50
9.8.3
Key Secondary Efficacy Endpoints .......................................................................51
9.8.4
Secondary Efficacy Endpoints...............................................................................52
9.8.5
Exploratory Efficacy Endpoints.............................................................................53
9.9
Safety Analyses........................................................................................................53
9.10
Other Analyses .........................................................................................................54
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................54
10.1
Sponsor’s Responsibilities .......................................................................................55
10.1.1 Good Clinical Practice Compliance.......................................................................55
10.1.2 Indemnity/Liability and Insurance.........................................................................55


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


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LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................18
Table 2  
Common Excluded Treatments and Associated Washout Periods................30
LIST OF FIGURES
Figure 1
SHP640-301 Study Design............................................................................24
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
HSV
Herpes Simplex Virus
ICH
International Conference on Harmonisation
IOP
intraocular pressure
IRB
Institutional Review Board
IRT
interactive response technology
ITT
Intent to Treat
mITT
Modified Intent to Treat
MRSA
methicillin-resistant Staphylococcus aureus
PVP-I
povidone-iodine
qPCR
quantitative polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment- emergent adverse event
US
United States


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STUDY SYNOPSIS
Protocol number: SHP640-301
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 100 sites across North America, South America, Asia/Pacific,
Europe, the Middle East and Africa.
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]) 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:

Adenovirus viral titer assessed by quantitative polymerase chain reaction (qPCR) at Visit 
3 (Day 6) and 4 (Day 8)

Adenoviral eradication as assessed by CC-IFA at Visits 4 (Day 8) and 5 (Day 12)

Clinical resolution  of adenoviral conjunctivitis at Visits 2 (Day 3), 4 (Day 8) and 5 (Day 
12) 

Individual clinical signs (bulbar conjunctival injection and watery conjunctival discharge) 
at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)


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
The global clinical score (sum of bulbar conjunctival injection and watery conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 6), 4 (Day 8) and 5 (Day 12). 

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)

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)

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 (Day 
8), and 5 (Day 12) 

To assess the status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected eye at 
baseline

To evaluate the safety and tolerability of SHP640 compared to 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 investigational product in each eye 4 times daily (with a minimum of 2 hours 
between doses) for 7 days.
Methodology:
Once screening and baseline assessments are complete and subjects are confirmed eligible to enroll in the study, 
subjects will be randomized, and investigational product will be administered on the same day (Day 1). The first 
dose will be administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 
times a day (QID) for 7 days. Additional visits will occur on Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), 
and Visit 5 (Day 12). The study will last up to 13 days. 
Inclusion and exclusion criteria: 
Inclusion Criteria:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions (by 
the parent(s), guardian, or legally authorized representative, if applicable).
2.
Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), guardian, or 
legally-authorized representative(s) informed consent (and assent, if applicable) to participate in the 
study.
3.
Subjects of any age at Visit 1 (Note: subjects <3 months of age at Visit 1 must have been full-term, ie 


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≥37 weeks gestational age at birth).
4.
Have a positive AdenoPlus® test at Visit 1 in at least 1 eye.
5.
Have a clinical diagnosis of suspected adenoviral conjunctivitis in at least 1 eye (the same eye as the 
AdenoPlus positive eye) confirmed by the presence of the following minimal clinical signs and 
symptoms in that same eye:

Report presence of signs and/or symptoms of adenoviral conjunctivitis for ≤ 3 days prior to Visit 1

Bulbar conjunctival injection: a grade of ≥1 (mild) on a 0-4 Bulbar Conjunctival Injection Scale.

Watery conjunctival discharge: a grade of ≥1 (mild) on a 0-3 Watery Conjunctival Discharge Scale
6.
Be willing to discontinue contact lens wear for the duration of the study.
7.
Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as measured using 
an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will be assessed by an age 
appropriate method in accordance with the AAP Policy Statement for Visual System Assessment in 
Infants, Children, and Young Adults by Pediatricians (Donahue and Baker 2016; American Academy 
of Pediatrics 2016). The policy statement recommends formal vision screening can begin at 3 years of 
age. VA measurements for children under the age of 3 will be done at the discretion of the investigator. 
If not done, child should be able to fixate on and follow a moving object, except subjects <2 months of 
age who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion of 
Investigator. 
8.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of non-childbearing potential. 
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1.
Current or recurrent disease that could affect the action, absorption, or disposition of the investigational 
product, or clinical or laboratory assessments, per investigator’s discretion.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may make the 
subject unlikely to fully complete the study, or any condition that presents undue risk from the 
investigational product or procedures.
3.
Have known or suspected intolerance or hypersensitivity to the investigational product, closely related 
compounds, or any of the stated ingredients. 
4.
Prior enrollment in a FST-100 or SHP640 clinical study.
5.
Subjects who are employees, or immediate family members of employees (who are directly related to 
study conduct), at the investigational site.
6.
Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned for the 
period of the study.
7.
Have a preplanned overnight hospitalization during the period of the study.
8.
Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, iritis, 
ulcerative keratitis, chronic blepharoconjunctivitis), other than adenoviral conjunctivitis.
9.
Have presence of corneal subepithelial infiltrates at Visit 1.
10. Have active or history of ocular herpes.
11. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with the 
diagnosis of ocular allergy, toxic conjunctivitis, or non-adenoviral ocular infection (eg, bacterial, 
fungal, acanthamoebal, other or parasitic).
12. Neonates or infants (ie. subjects less than 12 months of age) who have suspected or confirmed (based 
on the result of any test conducted prior to screening) conjunctivitis of gonococcal, chlamydial, 
herpetic or chemical origin.
13. Neonates or infants (ie. subjects less than 12 months of age) whose birth mothers had any sexually


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transmitted disease within 1 month of delivery or any history of genital herpes.
14. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
15. Presence of any significant ophthalmic condition (eg, Retinopathy of Prematurity, congenital cataract, 
congenital glaucoma) or other congenital disorder with ophthalmic involvement that could affect study 
variables.
16. Be a known intraocular pressure (IOP) steroid responder, have a known history of glaucoma, be a 
glaucoma suspect, or have a known history of an elevated IOP > 21 mmHg.
17. Have any known clinically significant optic nerve defects. 
18. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to previous 
corneal trauma or dry eye syndrome; presence of corneal epithelial defect or any significant corneal 
opacity at Visit 1.
19. Presence of significant, active condition in the posterior segment which requires invasive treatment (eg, 
intravitreal treatment with VEGF inhibitors or corticosteroids) and may progress during the study 
participation period.
20. Have used any topical ocular or systemic anti-virals or antibiotics within ≤7 days of enrollment. 
21. Have used any topical ocular NSAIDs within ≤1 day of enrollment.
22. Have used any topical ophthalmic steroids in the last ≤14 days.
23. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 days 
prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no anticipated change in 
dose for the duration of the study. Topical dermal steroids are allowed except in the peri-ocular area.
24. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
25. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all topical 
ophthalmic products for the duration of the study. Use of hot or cold compresses is also not permitted 
during the study.  
26. Have any significant ocular disease (eg, Sjogren's syndrome) or any uncontrolled systemic disease or 
debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted diseases/infections, 
diabetes or cystic fibrosis), that may affect the study parameters, per Investigator’s discretion.
27. Any known history of immunodeficiency disorder or known active conditions predisposing to 
immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of  active 
hepatitis A (antihepatitis A virus immunoglobulin M), or organ or bone marrow transplantation.
28. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study.
Maximum duration of subject involvement in the study:
Subject participation will last up to 13 days.
Screening, randomization and the first treatment administration will occur at Visit 1 (Day 1). 
Additional visits will occur on Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), and Visit 5 (Day 12). 
All follow-up procedures will be conducted at Visit 5 (Day 12).
Endpoints and statistical analysis:
Primary Efficacy Endpoint:
Clinical resolution status (defined as absence of bulbar conjunctival injection and watery conjunctival 
discharge) in the study eye at Visit 3 (Day 6) between SHP640 and placebo.
Key Secondary Efficacy Endpoints:
Clinical resolution status 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).


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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.
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 signs score (bulbar conjunctival injection and watery conjunctival discharge) 
and change from baseline at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the  study eye

The global clinical score (as defined as the sum of bulbar conjunctival injection and watery 
conjunctival discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 6), 4 (Day 8) and 5 (Day 12) in the  study eye

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 
(Day 6), 4 (Day 8) and 5 (Day 12) in the  study eye

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with neither injection
nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the  study 
eye

The status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye at Visits 2 (Day 3), 
3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected eye at baseline

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8), and 5 
(Day 12) in the study eye
Safety Endpoints:

Best Corrected Visual Acuity (BCVA)

Slit Lamp Biomicroscopy 

Non-dilated/ Dilated Fundus Examination

Urine Pregnancy Testing (for females of childbearing potential)

Adverse Events (AEs)
Statistical Methods:
The analyses on primary, key secondary, secondary and exploratory efficacy endpoints will be performed on the
mITT population (unless specified otherwise) and will be presented by treatment group. Additional sensitivity 
analyses may be conducted on the ITT population. Safety analysis will be conducted on the safety population.
For both efficacy and safety analyses, baseline is defined as the assessments taken at Visit 1 (Day 1).
Analyses Populations:
The Safety Population will include all subjects who receive at least one dose of investigational product
The Intent to Treat (ITT) Population will include all randomized subjects. 


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The Modified Intent to Treat (mITT) population consists of a subset of the ITT population who receive at 
least one dose of investigational product and have a positive CC-IFA adenovirus test at baseline in the study 
eye.
Designation of Study Eye:
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a score of at least 1 
for both watery conjunctival discharge and bulbar conjunctival redness at baseline (baseline is defined as the 
assessments taken at Visit 1 (Day 1):

For subjects with both eyes eligible and both with a positive CC-IFA result at baseline or both eyes 
eligible and both with a negative CC-IFA result at baseline, the study eye will be the eye with the 
highest global clinical score (sum of the scores for discharge and redness) at baseline. If both eyes have 
the same global clinical score at baseline, then the study eye will be the right eye.

For subjects with both eyes eligible with a positive CC-IFA result in one eye at baseline, the baseline 
CC-IFA positive eye will be the study eye.

For subjects with only one eligible eye, the eligible eye will be the study eye irrespective of its baseline 
CC-IFA status.
Primary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. There is a single 
primary comparison for the single primary endpoint. Therefore, no adjustment of multiplicity is needed for the 
hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 6) will be compared 
between the SHP640 and placebo group. The comparison will be based on the proportion of subjects with 
clinical resolution in the study eye at Visit 3 (Day 6) using Fisher’s Exact test at two sided 0.05 significance 
level. 
If subjects have missing clinical resolution status at Visit 3 (Day 6), then the last post-baseline observation will 
be carried forward (LOCF) for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with clinical resolution in 
the study eye between SHP640 Ophthalmic Solution and Placebo with the alternative of the non-zero difference 
in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with two-sided Fisher’s Exact test at 5% 
level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical method(s) 
including other methods of imputation of missing data. Sensitivity analyses may be conducted in the ITT in 
addition to the mITT.
Key Secondary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. 
In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary hypotheses will be 
tested sequentially using two-sided Fisher’s exact test according to the following sequence: 


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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 number of subjects (n), mean, median, standard deviation, minimum, maximum and 
confidence intervals.  Binary endpoints will be summarized by number of subjects (n), frequencies proportions 
and confidence intervals. Time to event endpoint will be summarized by Kaplan-Meier survival estimates.
Safety Analyses:
Safety data will be presented for the Safety Population by treatment group and overall. Adverse events will be 
coded using the Medical Dictionary for Regulatory Activities. The number of subjects and percentage with a 
treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated overall, by SOC, 
by preferred term, and by treatment group and overall. Treatment-emergent adverse events will be further 
summarized by severity and relationship to investigational product. Adverse events related to investigational 
product, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized and listed. Any AE that 
occurs after the first dose of investigational product instillation will be considered a TEAE.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or non-ocular AE.
BVCA, Slit Lamp Biomicroscopy, non-dilated/dilated fundus exam,  and urine pregnancy test (for females of 
childbearing potential) will be descriptively summarized by treatment group and overall at each applicable visit.


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Study Schedule
Table 1
Schedule of Assessments
Procedure
(All ocular assessments and 
procedures performed bilaterally)
Visit 1
Screeninga & 
Baseline
(Day 1)
-1 day
Visit 2
(Day 3)
Visit 3
(Day 6)
Visit 4 
(Day 8)
Visit 5b
(Day 12)
+1 day
Informed consent/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
Ocular Discomfort Scale
X
X
X
X
X
Best corrected visual acuity
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
Bulbar conjunctival injection 
evaluation
X
X
X
X
X
Watery conjunctival discharge 
evaluation
X
X
X
X
X
AdenoPlus®  test
Xd
Conjunctival swab for viral culturee
Xm
Xf
Xf
Xf
Xf
Conjunctival swab for bacterial 
cultureg
X
Xfg
Xf
Non-dilated/ dilated fundus 
examinationh
X
X
Randomizationi
X
Dispense investigational product j
X
Instill investigational product
Xj
Xk
Xk
Collect investigational product
X
Xb
Compliance assessment
X
X
X
Xb
Drug accountability
X
Xb
Adverse events
Xl
X
X
X
X
Study completion
X


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Table 1
Schedule of Assessments
Procedure
(All ocular assessments and 
procedures performed bilaterally)
Visit 1
Screeninga & 
Baseline
(Day 1)
-1 day
Visit 2
(Day 3)
Visit 3
(Day 6)
Visit 4 
(Day 8)
Visit 5b
(Day 12)
+1 day
CC-IFA= cell culture-immunofluorescence assay; HSV= herpes simplex virus; qPCR= quantitative polymerase 
chain reaction; 
a Informed consent and confirmation of inclusion/exclusion criteria can be conducted on Day -1; Inclusion/Exclusion 
must be re-confirmed on Day 1
b If investigational product is discontinued, regardless of the reason, all discontinued subjects should proceed to Visit 
5 whenever possible. Subjects that discontinue the study and proceed to Visit 5 should perform all Visit 5 
assessments as well as drug return, compliance and accountability.
c Women of childbearing potential, prior to enrollment and at exit from the study.
d If not previously conducted within 24 hours of Visit 1 (Day 1)
e One swab sample from inferior conjunctival cul-de-sac of each eye will be collected for all viral testing. If the CC-
IFA test is positive, qPCR will be performed. Adenoviral serotyping will be conducted at baseline only.
f Conjunctival swab samples MUST be taken at least 12 hours after the last dose of investigational product at Visits 
2, 3, 4 and ET, if applicable.
g One swab sample from each conjunctival cul-de-sac will be collected for all bacterial testing.
h If a non-dilated fundus exam is not feasible, a dilated examination should be conducted. For each subject, the exam 
should be conducted the same way (either non-dilated or dilated) at both Visit 1 and Visit 5 (or ET).    
i All assessments, randomization, and investigational product  instillation on Day 1 must take place with sufficient 
time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses)
.j The investigational product bottle should be shaken well prior to use at each dosing. The first dose will be 
administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a day for 7 
days.
k Investigational product instillation should only be performed in-office if it is necessary.
l Monitoring for adverse events will begin after informed consent is obtained.
m This sample will be used for baseline HSV testing for all subjects. For subjects <2 months of age, testing will also 
be conducted using the same sample for chlamydia and gonorrhea detection.


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Conjunctivitis affects all populations worldwide of all ages and social strata, irrespective of 
gender. Within infectious conjunctivitis, viral etiology may account for up to 80% of all cases in 
adults and bacterial conjunctivitis is the second most common cause of infectious conjunctivitis 
overall. Infectious conjunctivitis represents a serious public health issue due to a risk of highly 
infectious epidemics, lost productivity, significant patient discomfort, and in some cases 
permanent visual compromise from long-term, immune-mediated sequelae (Ford et al., 1987; 
Nauheim et al., 1990; Gordon et al., 1993; Pelletier et al., 2009; Capriotti et al., 2010).
Adenoviruses, unlike bacteria, are not part of the normal flora of the ocular surface and their 
presence is indicative of an infection (Cambon and Pollard, 1959; Willamson et al., 1975; 
Vastine et al., 1977; Gigliotti et al., 1981; Kaneko et al., 2008). It is the most reported cause of 
viral conjunctivitis in up to 75% of cases (Wilkins et al., 2011). Adenoviral conjunctivitis is 
typically spread through direct contact between the eye and hands that are contaminated with the 
virus via contact with infected eye discharge, fecal matter, or respiratory discharge (CDC, 2010). 
Given the highly transmittable nature of the disease, it is not surprising that it is observed to be 
most prevalent in densely populated, overcrowded areas, or in the presence of poor hygiene, or 
both (Capriotti et al., 2010).
Adenoviral conjunctivitis typically lasts 14-21 days (Wilkins et al., 2011). The onset is usually 
rapid and the infection often spreads from one eye to the other (AAO Cornea/External Disease 
PPP Panel, 2013). 
Currently, there are no approved treatments for adenoviral conjunctivitis; therapeutic options are 
limited to supportive therapies and palliative measures such as cold compresses, artificial tears, 
and topical antihistamines (AAO Cornea/External Disease PPP Panel, 2013). This Phase 3 study 
is being conducted to evaluate the clinical efficacy and safety of SHP640 for the treatment of 
adenoviral conjunctivitis.
1.2
Product Background and Clinical Information
SHP640, a novel topical ophthalmic suspension, is currently under development for the treatment 
of infectious conjunctivitis (adenoviral and bacterial).
SHP640 contains 2 active ingredients: povidone-iodine (PVP-I) and dexamethasone. PVP-I is a 
multivalent broad-spectrum local antiseptic with bactericidal and fungicidal properties. The 
effect on vegetative cells of various bacteria and fungi is due to the liberation of free iodine from 
the complex. It is effective against many viruses, protozoa, yeasts, cysts, and spores (Betadine, 
2004). Dexamethasone is a corticosteroid routinely used as a topical ophthalmic suspension for
the treatment of ocular inflammation. It suppresses the inflammatory response to a variety of 
causes of inflammation (Maxidex, 2007). Both components are currently approved for use in 
other indications (at similar or higher concentrations) and have been shown to be safe and 
efficacious for use on the ocular surface in humans. The combination of PVP-I and 


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dexamethasone has been shown to rapidly kill common ocular pathogens, including viruses, 
gram-positive bacteria (including MRSA), and gram-negative bacteria (Pelletier et al., 2011).
Always refer to the latest version of the SHP640 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy and safety of SHP640. 
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The clinical presentation of conjunctivitis is often nonspecific and differential diagnosis of 
different types of conjunctivitis can be challenging (Azari and Barney, 2013; O'Brien et al., 
2009). Diagnostic testing to differentiate the underlying cause of infection is rarely performed in 
a clinical setting; misdiagnosis can occur in up to 50% of cases, which often results in improper 
antibiotic treatment (Visscher et al., 2009). Incorrect treatment can not only increase healthcare 
costs from unnecessary antibiotic prescriptions and repeat office visits, but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or methicillin-
resistant Staphylococcus aureus [MRSA]). In addition, there is also a risk of overuse and misuse 
of antibiotics, which are ineffective in the treatment of viral infections (Statham et al., 2008). 
Currently there is no approved medication for the treatment of adenoviral conjunctivitis. An 
unmet medical need therefore exists for a safe and efficacious treatment that addresses both 
bacterial and adenoviral conjunctivitis, two of the leading causes of acute infectious 
conjunctivitis.
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, 
with dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious 
and inflammatory components of adenoviral and bacterial conjunctivitis.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical 
resolution (defined as absence of bulbar conjunctival injection and watery conjunctival 
discharge) compared with placebo in the treatment of subjects with adenoviral conjunctivitis in 
the study eye at Visit 3 (Day 6). 
2.2.2
Key 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]) compared with placebo in the treatment of 
subjects with adenoviral conjunctivitis in the study eye at Visit 2 (Day 3).


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
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).
Adenoviral eradication is defined in Section 7.2.2.
2.2.3
Secondary Objectives
Secondary objectives of this study are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints:

Adenovirus viral titer assessed by quantitative polymerase chain reaction (qPCR) at 
Visit 3 (Day 6) and 4 (Day 8)

Adenoviral eradication as assessed by CC-IFA at Visits 4 (Day 8) and 5 (Day 12)

Clinical resolution of adenoviral conjunctivitis at Visits 2 (Day 3), 4 (Day 8) and 5 (Day 
12)

Individual clinical signs (bulbar conjunctival injection and watery conjunctival 
discharge) at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)

The global clinical score (sum of bulbar conjunctival injection and watery conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 6), 4 (Day 8) and 5 (Day 12). 

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)

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)

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 
(Day 8), and 5 (Day 12) 

To assess the status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye
at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected eye at 
baseline

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the 
treatment of subjects with adenoviral conjunctivitis


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2.2.4
Exploratory Objectives
The exploratory objectives of this study are as follows: 
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 will be randomized into the study at Visit 1 (Day 1). Subjects will 
be randomized 2:2:1 to receive either SHP640, PVP-I, or placebo within each stratum. 
Randomization will be stratified by age to maintain the randomization ratio among subjects < 6 
years, 6 to <18 years and subjects ≥18 years.
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced randomization will be used in this study to 
maintain the randomization ratio within each stratum. 
Once screening and baseline assessments are complete and subjects are confirmed eligible to 
enroll in the study, subjects will be randomized, and investigational product will be administered 
on the same day (Day 1). The first dose will be administered by site staff on Day 1, and 
thereafter subjects will administer 1 drop in each eye 4 times a day (QID) for 7 days. Additional 
visits will occur on Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), and Visit 5 (Day 12). All 
follow-up procedures will be conducted at Visit 5 (Day 12). The study will last up to 13 days. 
Figure 1 provides the study design.


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Figure 1
SHP640-301 Study Design
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 100 sites across North America, South America, 
Asia/Pacific, Europe, the Middle East, and Africa.
4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed. If a subject is younger 
than the legal age of consent (per local laws), the subject's parent(s), guardian, or legally 
authorized representative will provide written informed consent; the subject will provide verbal 
or written assent as appropriate.
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).


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2. Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), 
guardian, or legally-authorized representative(s) informed consent (and assent, if applicable) 
to participate in the study.
3. Subjects of any age at Visit 1 (Note: subjects < 3 months of age at Visit 1 must have been 
full-term, ie ≥37 weeks gestational age at birth).
4. Have a positive AdenoPlus® test at Visit 1 in at least 1 eye.
5. Have a clinical diagnosis of suspected adenoviral conjunctivitis in at least 1 eye (the same 
eye as the AdenoPlus positive eye) confirmed by the presence of the following minimal 
clinical signs and symptoms in that same eye:

Report presence of signs and/or symptoms of adenoviral conjunctivitis for ≤ 3 days 
prior to Visit 1

Bulbar conjunctival injection: a grade of ≥1 on 0-4 scale of Bulbar Conjunctival 
Injection Scale

Watery conjunctival discharge: a grade of ≥1 (mild) on a 0-3 Watery Conjunctival 
Discharge Scale
6. Be willing to discontinue contact lens wear for the duration of the study.
7. Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as 
measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will 
be assessed by an age appropriate method in accordance with the AAP Policy Statement for 
Visual System Assessment in Infants, Children, and Young Adults by Pediatricians 
(Donahue and Baker, 2016; American Academy of Pediatrics, 2016). The policy statement 
recommends formal vision screening can begin at 3 years of age. VA measurements for 
children under the age of 3 will be done at the discretion of the investigator. If not done, child 
should be able to fixate on and follow a moving object, except subjects <2 months of age 
who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion 
of Investigator. 
8. Male, or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Current or recurrent disease that could affect the action, absorption, or disposition of the 
investigational product, or clinical or laboratory assessments, per investigator’s discretion.
2. Current or relevant history of physical or psychiatric illness, any medical disorder that may
make the subject unlikely to fully complete the study, or any condition that presents undue 
risk from the investigational product or procedures.
3. Have known or suspected intolerance or hypersensitivity to the investigational product, 
closely related compounds, or any of the stated ingredients. 


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


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23. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 
days prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no 
anticipated change in dose for the duration of the study. Topical dermal steroids are allowed 
except in the peri-ocular area.
24. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
25. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all 
topical ophthalmic products for the duration of the study. Use of hot or cold compresses is 
also not permitted during the study.
26. Have any significant ocular disease (eg, Sjogren's syndrome) or any uncontrolled systemic 
disease or debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted 
diseases/infections, diabetes or cystic fibrosis), that may affect the study parameters, per 
Investigator’s discretion.
27. Any known history of immunodeficiency disorder or known active conditions predisposing 
to immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of  
active hepatitis A (antihepatitis A virus immunoglobulin M), or organ or bone marrow 
transplantation.
28. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception throughout the study period. If hormonal contraceptives are used, they should be 
administered according to the package insert. Females of childbearing potential who are not 
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.


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Adult female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and ≥age 51 years)

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of childbearing potential with a negative urine pregnancy test at Visit 1 and prior to 
randomization. Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use acceptable methods of contraception. 
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Intrauterine hormone-releasing systems plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam) 

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the screening visit (Visit 1), plus condoms.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, if in the judgment of the investigator, there is no clinical 
improvement or worsening to an extent that it would be in the best interest of the subject to be 
treated with an alternate therapy for safety reasons). The investigator is encouraged to discuss 
withdrawal of a subject from investigational product with the medical monitor if necessary.
If investigational product is discontinued for any reason other than a positive HSV baseline test, 
the evaluations listed for Visit 5 are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified follow-up (proceed 
to Visit 5). Comments (spontaneous or elicited) or complaints made by the subject must be 
recorded in the source documents. The reason for termination and the date of stopping 
investigational product must be recorded in the case report form (CRF) and source documents.
Subjects who test positive for ocular HSV at baseline in either eye should have their 
investigational product discontinued, and should receive alternate appropriate treatment as 
needed based on the Investigator’s judgment. These subjects should be followed for the 
remaining duration of study at regularly scheduled visits, and all safety related assessments 
should be completed (AEs, BCVA, slit lamp biomicroscopy at all visits; fundus exam at Visit 5).
If a subject <2 months of age has a positive CT-NG test for any one of the two Visit 1 samples, 
the subject will be discontinued from the study and started with alternate standard of care therapy 
per the Investigator’s clinical judgment. 


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


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5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment other than the investigational production taken 
between the dates of the first dose of investigational product and the end of Visit 5 (the end of 
study visit), inclusive. Concomitant treatment information must be recorded on the appropriate 
CRF page.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol.  In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
Medications not indicated as prohibited are permitted, including treatments for general 
non-excluded medical conditions.
In the event of an emergency, any needed medications may be prescribed without prior approval, 
but the medical monitor must be notified of the use of any prohibited medications immediately 
thereafter.
5.2.2
Prohibited Treatment
Table 2 details the washout period for common prior treatments that are excluded medications 
for this study. 
Table 2  
Common Excluded Treatments and Associated Washout Periods
Minimum Time Prior to First 
Dose
Notes
Treatment
30 
days 
14 
days
7 
days
1 
day
2 
hours
Topical ocular NSAIDs
X
Topical ocular or systemic anti-virals
X
Topical ophthalmic steroids
X
Systemic corticosteroid agents
X
Stable use of inhaled or nasal 
corticosteroids
X
Allowed ≥30 days if no 
anticipated dose changes 
during the study
Non-corticosteroid 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, IMP returns, accountability of 
IMP, and emergency unmasking.
6.2.2
Allocation of Subjects to Treatment 
This is a double-masked, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment is 
automatically assigned by the IRT.
Randomization will be stratified by age to maintain the randomization ratio among subjects < 6 
years, 6 to <18 years and subjects ≥18 years.  Subjects will be randomly assigned to receive 
SHP640, PVP-I 0.6%, or placebo based on a 2:2:1 ratio [SHP640: PVP-I 0.6%: placebo] within 
the randomization strata.


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


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


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


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


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7.1.1
Visit 1 (Day 1)
Screening and baseline/randomization will occur at Visit 1. Visit 1 assessments, beginning with 
informed consent, will be performed as outlined in Table 1.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product. Subjects cannot be rescreened once they have been designated as a 
screen failure.
A urine pregnancy test will be completed for all females of childbearing potential.  The results 
will be read by site personnel and recorded in the source documents.
All AEs occurring after signature of informed consent must be recorded in the source documents 
and CRF. 
Prior to randomization, the procedures should be performed in the following order (in both eyes, 
as appropriate):

Informed consent (and assent, if applicable)

Inclusion/exclusion criteria

Medical history

Demographics

Concomitant medications

Urine pregnancy test (for women of childbearing potential)

Ocular Discomfort Scale

Best corrected visual acuity

Slit lamp biomicroscopy

Bulbar conjunctival injection evaluation

Watery conjunctival discharge evaluation

AdenoPlus® test (if not previously conducted within 24 hours of Visit 1) 
If any findings during screening exams do not meet the inclusion/exclusion criteria, the subject is 
not eligible to be randomized. 
Eligible subjects must have a positive response in at least one eye.  A positive response is 
defined as meeting ALL of the following criteria in the same eye:

Report presence of signs and/or symptoms of adenoviral conjunctivitis for ≤ 3 days prior to 
Visit 1


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
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) 

Non-dilated/ dilated fundus examination

Randomization

Dispense and instill investigational product in both eyes by the designated site staff 
investigational product administrator. The investigational product bottle should be shaken 
well prior to use at each dosing
In order to ensure QID dosing on Day 1 (with a minimum of 2 hours between doses), all 
assessments, randomization, and investigational product instillation on Day 1 must take place 
with sufficient time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses).
7.1.2
Visit 2 (Day 3), Visit 3 (Day 6), and Visit 4 (Day 8)
Visit 2 (Day 3), Visit 3 (Day 6), and Visit 4 (Day 8) assessments will be performed as outlined in 
Table 1 and as described in the Study Operations Manual. Assessments should be performed in 
descending order as listed.
Subject compliance will be verified verbally during study visits. In cases of non-compliance the 
investigator should determine if the medical monitor must be contacted for consultation. 
Subjects should not instill investigational product within 12 hours of scheduled Study Visits. To 
ensure this, subjects should be reminded to not dose the morning of Visits 2, 3 and 4. 
Investigational product instillation should only be performed in-office if it is necessary, and 
should be done once all other assessments are completed. Subjects who instill investigational 
product less than 12 hours before study visits will be recorded as protocol deviations.
7.1.3
Visit 5 (End of Study or Early Termination)
Safety follow-up will be conducted at Visit 5 (the end of study visit). Visit 5 (Day 12) 
assessments will be performed as outlined in Table 1. Assessments should be performed in 
descending order as listed.


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Subjects who discontinue the study and proceed to Visit 5 for early termination should have 
investigational product collected, a compliance assessment, and drug accountability assessed at 
their final visit.
All AEs and SAEs that are not resolved at the time of Visit 5 or early termination will be 
followed to closure (see Section 8.1).
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
7.2.1.1
Demographics
Demographic information will be collected at Visit 1. Date of Birth (where permitted), Age, Sex, 
Race, and Ethnicity will be recorded.
7.2.1.2
Medication and Medical History
MEDICATION HISTORY
Refer to Section 5 for full details on collection of prior treatment.
The investigator will categorize treatments as ocular (specified as left eye, right eye or both eyes) 
or non-ocular based on the indication for use.  Prior treatment information must be recorded on 
the appropriate CRF page.  
MEDICAL HISTORY
The site must record all clinically or medically relevant information regardless of how much time 
has elapsed since the date of any diagnosis. Medical history will be classified as ocular (specified 
as left eye, right eye or both eyes) or non-ocular by the investigator. History should include, but 
is not limited to: 

History of ocular diseases/conditions. 

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, and any other non-ocular diseases/underlying conditions within 
the past year prior to the Screening Visit (Visit 1).
7.2.1.3
AdenoPlus Test
The AdenoPlus test will be performed at Visit 1 as outlined in Table 1. A positive result in at 
least one eye is required for enrollment in this study.
The AdenoPlus test is an in-office test that allows for the detection of adenoviral antigens 
directly from human eye fluid. A small tear sample is transferred onto the AdenoPlus test, which 
confirms the presence of adenovirus and the viral form of conjunctivitis. 


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Please refer to the Operations Manual for a detailed description of the AdenoPlus Test and 
administration.
7.2.2
Efficacy
7.2.2.1
Clinical Resolution
Clinical resolution of adenoviral conjunctivitis is defined as the absence (score = 0) of bulbar 
conjunctival injection and watery conjunctival discharge in the study eye. Bulbar Conjunctival 
Injection will be assessed based on a 0-4 scale which uses pictures from the Validated Bulbar 
Redness (VBR) Scale and Watery Conjunctival Discharge will be assessed based on a 0-3 scale. 
Details of the Bulbar Conjunctival Injection and Watery Conjunctival Discharge scales are 
located in the study Operations Manual.
7.2.2.2
Adenoviral Eradication
Adenoviral eradication for an eye is defined as negative CC-IFA in that eye.  CC-IFA for each 
eye will be conducted using conjunctival swab samples collected at each visit. See the 
Laboratory Manual for further details.
7.2.3
Safety
Safety assessments will be performed in both eyes.
7.2.3.1
Best Corrected Visual Acuity (BCVA)
The BCVA will be performed prior to slit lamp examination during the study as outlined in 
Table 1.
The complete instructions for performing the BCVA are in the Operations Manual. Changes in 
VA will be assessed for clinical significance. Clinically significant changes should be recorded 
in the source and on the eCRF as an AE.
For subjects who are too young to use an ETDRS chart, use an age-appropriate measurement 
method in accordance with the AAP Policy Statement for Visual System Assessment in Infants, 
Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American Academy of 
Pediatrics, 2016; located in the Operations Manual). The policy statement recommends formal 
vision screening can begin at 3 years of age. VA measurements for children under the age of 3 
will be done at the discretion of the investigator. If not done, child should be able to fixate on 
and follow a moving object. This is not a requirement in subjects <2 months of age since the 
ability does not develop until about 2 months of age. However, if an infant <2 months of age is 
able to fix and follow, it should be recorded. The enrollment of subjects <2 months of age will be 
based on subject qualifying all other eligibility criteria and Investigator discretion.
VA is to be measured using the same method at all visits in the same subject.


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7.2.3.2
Slit Lamp Biomicroscopy
Slit lamp biomicroscopy (or hand held slit lamp) will be performed during the study as outlined 
in Table 1. Magnification of the slit lamp will be consistent with standard clinical practice. The 
subject will be seated.
Observations will be graded as Normal or Abnormal. Abnormal findings will be described, and 
clinically significant abnormalities should be recorded in the source and on the electronic CRF 
(eCRF) (in Medical History at Screening; any changes from the screening visit may be recorded 
as adverse events by the investigator). Please note the investigator may use his/her discretion to 
determine whether Not Clinically Significant (NCS) and disease progression should be 
considered AEs). The following will be examined at each visit: 

Lids 

Conjunctiva 

Cornea

Anterior Chamber

Iris

Lens
For infants and young children, if the above exams cannot be performed with a slit lamp or a 
hand held slit lamp, an external examination is to be conducted in accordance with American 
Academy of Pediatrics (AAP) Policy Statement for Visual System Assessment in Infants, 
Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American Academy of 
Pediatrics, 2016; located in the Operations Manual). The examination of lens in these subjects 
should be conducted at Visit 1 and Visit 5 (or ET visit) and graded based on the external 
examination and red reflex exam (Section 7.2.3.3). All other structures listed above will be 
examined and graded at all visits based on the external examination. Observations will be graded 
as Normal or Abnormal. Abnormal findings will be described.
7.2.3.3
Non-dilated/ Dilated Fundus Examination
Fundus examination must be conducted after BCVA, Slit Lamp Biomicroscopy and conjunctival 
swab for adenoviral and bacterial culture has been collected. 
A non-dilated fundus examination will be performed in all subjects with the exception of infants 
and uncooperative small children during the study as outlined in Table 1.
Observations will be graded as Normal or Abnormal. Abnormal findings will be described.
The following will be examined:

Vitreous

Optic Nerve


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
Macula
Clinically significant changes should be recorded in the source and on the eCRF as an AE.
If a non-dilated fundus exam is attempted and is not feasible, dilated fundus exam should be 
conducted. The test should be conducted the same way (either dilated or non-dilated) at both 
Visit 1 and Visit 5 (or ET).
For infants and small children in whom a fundus examination cannot be done, a red reflex exam 
will be conducted in accordance with AAP Policy Statement for Visual System Assessment in 
Infants, Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American 
Academy of Pediatrics, 2016; located in the Operations Manual). Observations will be graded as 
Normal or Abnormal. Abnormal findings will be described. The red reflex should be normal 
(present and symmetrical for both eyes) at the screening/ baseline visit. 
7.2.3.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.) Any AE that occurs after the first dose of 
investigational product instillation will be considered a TEAE.
Adverse events may also be determined by the investigator during study examinations as 
mentioned in previous sections.
7.2.3.5
Microbiology Laboratory Evaluations
All laboratory assays will be performed according to the laboratory’s normal procedures. 
All bioanalytical assays for the study will be validated following FDA/ICH guidelines, based on 
the method's intended use. The 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 laboratory assessments will be performed: 

Cell Culture 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.

qPCR: This test will be performed on samples for qualitative detection of HSV at baseline 
(Visit 1). 


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One swab sample from each eye will be taken from inferior conjunctival cul-de-sac at all study 
visits for adenoviral testing. For neonates and infants <2 months of age, PCR testing for
qualitative detection of chlamydia and gonorrhea at baseline will also be conducted using the 
baseline visit sample.
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 three items: pain, itching, and 
foreign body sensation. All items will be evaluated using a 0-10 scale. A separate scale will be 
administered for children less than 8 years of age (binary ocular discomfort). Please see the 
Operations Manual for a detailed description of this assessment.
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.


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8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
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 


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investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
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.


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


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8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure, which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO/Shire medical monitor 
within 24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see 
Section 8.1.6) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the CRO/Shire medical monitor using the details specified in the emergency 
contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
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 


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surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject provides 
written informed consent (and assent, if applicable) until the defined follow-up period stated in 
Section 7.1.3 and must be reported to the Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.
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.


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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.
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. 


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The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
The SAP will be finalized prior to unmasking of the study to preserve the integrity of the 
statistical analysis and study conclusions. 
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. 
The assumed proportions of subjects with clinical resolution in the 3 treatment arms are based on 
response rates observed in FST100-AVC-004 with a dropout rate of approximately 6% prior to 
Visit 3 in FST100-AVC-004 mITT population which excluded subjects with no post baseline 
data. The dropout rate would become approximately 8% if FST100-AVC-004 mITT population 
included subjects with no post baseline data.
All efficacy analyses will be based on the mITT population with post-baseline LOCF for the 
subjects with missing clinical resolution status at Visit 3 (Day 6).  To ensure 605 subjects in the 


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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 investigational product and have a positive CC-IFA adenovirus 
test at baseline in the study eye.
9.8
Efficacy Analyses
The analyses on primary, key secondary, secondary and exploratory efficacy endpoints will be 
performed on the mITT population (unless specified otherwise) and will be presented by 
treatment group. 
Additional sensitivity analyses may be conducted in the ITT population.
Efficacy data collected at Baseline (Visit 1 [Day 1]) will be used as the baseline for both efficacy 
and safety analyses. For both efficacy and safety analyses, baseline is defined as the assessments 
taken at Visit 1 (Day 1).
9.8.1
Study Eye Designation
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a 
score of at least 1 for both watery conjunctival discharge and bulbar conjunctival redness at 
baseline (baseline is defined as the assessments taken at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive CC-IFA result at baseline or 
both eyes eligible and both with a negative CC-IFA result at baseline, the study eye will be 
the eye with the highest global clinical score (sum of the scores for discharge and redness) at 
baseline. If both eyes have the same global clinical score at baseline, then the study eye will 
be the right eye. 

For subjects with both eyes eligible with a positive CC-IFA result in one eye at baseline, the 
baseline CC-IFA positive eye will be the study eye. 

For subjects with only one eligible eye, the eligible eye will be the study eye irrespective of 
its baseline CC-IFA status.
9.8.2
Primary Efficacy Endpoint
The primary efficacy endpoint is clinical resolution status (defined as absence [ie a score of 0] of 
bulbar conjunctival injection and watery conjunctival discharge) in the study eye at Visit 3 (Day 
6) between SHP640 and placebo.


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All efficacy analyses will be performed on the mITT and presented by treatment groups. There is 
a single primary comparison for the single primary endpoint. Therefore, no adjustment of 
multiplicity is needed for the hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 6) will be 
compared between the SHP640 and placebo group. The comparison will be based on the 
proportion of subjects with clinical resolution in the study eye at Visit 3 (Day 6) using Fisher’s 
Exact test at two sided 0.05 significance level. 
If subjects have missing clinical resolution status at Visit 3 (Day 6), then the last post-baseline 
observation will be carried forward (LOCF) for the determination of clinical resolution of the 
study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with 
clinical resolution in the study eye between SHP640 Ophthalmic Solution and Placebo with the 
alternative of the non-zero difference in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with two-sided Fisher’s 
Exact test at 5% level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical 
method(s) including other methods of imputation of missing data. Sensitivity analyses may be 
conducted in the ITT in addition to the mITT. In addition, descriptive statistics will be generated 
for the primary efficacy endpoint by treatment within the overall pediatric population (ie birth to 
18 years) and within each pediatric age stratum (birth to <6 years and 6 to <18 years) in mITT. A 
detailed plan for primary analysis including additional sensitivity analyses will be described in 
the Statistical Analysis Plan (SAP).
9.8.3
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints of this study are clinical resolution status 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.


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5. Comparison of proportion of subjects achieving clinical resolution between PVP-I and 
Placebo.
All efficacy analyses will be performed on the mITT and presented by treatment groups. In order 
to maintain the study-wide Type I error at 5.0%, the primary and key secondary hypotheses will 
be tested sequentially using two-sided Fisher’s exact test according to the following sequence: 
Sensitivity analyses will also be done on key secondary efficacy endpoints using similar methods 
as described above. In addition, descriptive statistics will be generated for the key secondary 
efficacy endpoint by treatment within the overall pediatric population (ie birth to 18 years) and 
within each pediatric age stratum (birth to < 6 years and 6 to <18 years) in mITT. Details on the 
analyses will be described in the Statistical Analysis Plan (SAP).
9.8.4
Secondary Efficacy Endpoints
All secondary efficacy analyses will be performed on the mITT and presented by treatment 
group.  No hypothesis testing is planned for the secondary efficacy endpoints.  All secondary 
efficacy endpoint will be summarized by treatment groups using descriptive statistics at each 
assessment visit.  Continuous endpoints will be summarized by number of subjects (n), mean, 
median, standard deviation, minimum, maximum and confidence intervals.  Binary endpoints 
will be summarized by number of subjects (n), frequencies, proportions and confidence intervals. 
Time to event endpoint will be summarized by Kaplan-Meier survival estimates.
Secondary efficacy endpoints are defined as follows:

Absolute and change from baseline in adenovirus viral titer as assessed by qPCR at 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 
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
The Individual clinical signs score (bulbar conjunctival injection and watery conjunctival 
discharge) and change from baseline at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)
in the study eye

The global clinical score (defined as the sum of bulbar conjunctival injection and 
watery conjunctival discharge) and change from baseline in the global clinical score 
at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the study eye

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the study eye

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with 
neither injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 6), 4 
(Day 8) and 5 (Day 12) in the study eye

The status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 
infected eye at baseline

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 
(Day 8), and 5 (Day 12) in the study eye
9.8.5
Exploratory Efficacy Endpoints
9.9
Safety Analyses
Safety data will be presented for the Safety Population by treatment group and overall.
Safety data collected at baseline (Visit 1 / Day 1) will be used as the baseline value for safety 
analysis.
Adverse events, including those suggestive of any local tolerability issues, will be coded using 
the Medical Dictionary for Regulatory Activities. The number of subjects and percentage with a 
treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated 
overall, by SOC, by preferred term, and by treatment group and overall. Treatment-emergent 
adverse events will be further summarized by severity and relationship to investigational 


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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 and overall 
at each applicable visit:

Best Corrected Visual Acuity (BCVA)

Slit Lamp Biomicroscopy

Lids 

Conjunctiva 

Cornea 

Anterior Chamber 

Iris

Lens 

Non-dilated/ Dilated Fundus Examination

Vitreous 

Optic Nerve 

Macula 

Urine Pregnancy Testing (for females of childbearing potential)
9.10
Other Analyses
No other analyses are planned in this study.
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.
In case of substantial amendment, approval from the Competent Regulatory Authority will be 
sought before implementation.  
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.


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10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC and its 
updates, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current good clinical practice (GCP) and the 
respective local and (inter)national government regulations and guidelines. Records and data 
may additionally be reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 


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


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


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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.
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.


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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.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.


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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
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.


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


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11.
REFERENCES
AAO Cornea/External Disease PPP Panel 2013. American Academy of Ophthalmology (AAO), 
2013 - Cornea/External Disease Preferred Practice Pattern Guidelines. Conjunctivitis. 
San Francisco, CA.
American Academy of Pediatrics 2016. Visual system assessment in infants, children, and young 
adults by pediatricians. Pediatrics, 137, 28-30.
Azari, A. A. & Barney, N. P. 2013. Conjunctivitis: a systematic review of diagnosis and 
treatment. Jama, 310, 1721-9.
Betadine 2004. Betadine Prescribing Information.
Cambon, E. N. & Pollard, M. 1959. Viral studies of the normal eye. Arch Ophthalmol, 62, 562-5.
Capriotti, J. A., Stewart, K. P. & Pelletier, J. 2010. The unique challenges of viral conjunctivitis -
Its similarities to bacterial infection belie key differences that impact clinical care 
[Online]. Ophthalmology Management. Available: 
http://www.ophthalmologymanagement.com/articleviewer.aspx?articleid=104651.
CDC. 2010. Conjunctivitis (pink eye) [Online]. Centers for Disease Control and Prevention. 
Available: http://www.cdc.gov/conjunctivitis/clinical.html.
Donahue, S. P. & Baker, C. N. 2016. Procedures for the Evaluation of the Visual System by 
Pediatricians. Pediatrics, 137.
Ford, E., Nelson, K. E. & Warren, D. 1987. Epidemiology of epidemic keratoconjunctivitis. 
Epidemiol Rev, 9, 244-61.
Gigliotti, F., Williams, W. T., Hayden, F. G., Hendley, J. O., Benjamin, J., Dickens, M., 
Gleason, C., Perriello, V. A. & Wood, J. 1981. Etiology of acute conjunctivitis in 
children. J Pediatr, 98, 531-6.
Gordon, Y. J., Gordon, R. Y., Romanowski, E. & Araullo-Cruz, T. P. 1993. Prolonged recovery 
of desiccated adenoviral serotypes 5, 8, and 19 from plastic and metal surfaces in vitro. 
Ophthalmology, 100, 1835-9; discussion 1839-40.
Kaneko, H., Maruko, I., Iida, T., Ohguchi, T., Aoki, K., Ohno, S. & Suzutani, T. 2008. The 
possibility of human adenovirus detection from the conjunctiva in asymptomatic cases 
during nosocomial infection. Cornea, 27, 527-30.
Maxidex 2007. Maxidex Prescribing Information.
Nauheim, R. C., Romanowski, E. G., Araullo-Cruz, T., Kowalski, R. P., Turgeon, P. W., Stopak, 
S. S. & Gordon, Y. J. 1990. Prolonged recoverability of desiccated adenovirus type 19 
from various surfaces. Ophthalmology, 97, 1450-3.
O'Brien, T. P., Jeng, B. H., McDonald, M. & Raizman, M. B. 2009. Acute conjunctivitis: truth 
and misconceptions. Curr Med Res Opin, 25, 1953-61.
Pelletier, J. S., Miller, D., Liang, B. & Capriotti, J. A. 2011. In vitro efficacy of a povidone-
iodine 0.4% and dexamethasone 0.1% suspension against ocular pathogens. J Cataract 
Refract Surg, 37, 763-6.
Pelletier, J. S., Stewart, K., Trattler, W., Ritterband, D. C., Braverman, S., Samson, C. M., Liang, 
B. & Capriotti, J. A. 2009. A combination povidone-iodine 0.4%/dexamethasone 0.1% 
ophthalmic suspension in the treatment of adenoviral conjunctivitis. Adv Ther, 26, 776-
83.
Pocock, S. J. & Simon, R. 1975. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 31, 103-15.


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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).

Prot_001.pdf: 
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
Amendment 1: 28 November 2016
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.






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


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
TABLE OF CONTENTS.................................................................................................................5
LIST OF TABLES...........................................................................................................................9
LIST OF FIGURES .........................................................................................................................9
LIST OF APPENDICES..................................................................................................................9
ABBREVIATIONS .......................................................................................................................10
STUDY SYNOPSIS ......................................................................................................................11
1.
BACKGROUND INFORMATION.......................................................................................20
1.1
Indication and Current Treatment Options...............................................................20
1.2
Product Background and Clinical Information ........................................................20
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................22
2.1
Rationale for the Study.............................................................................................22
2.2
Study Objectives ......................................................................................................22
2.2.1
Primary Objective..................................................................................................22
2.2.2
Key Secondary Objectives.....................................................................................22
2.2.3
Secondary Objectives.............................................................................................23
2.2.4
Exploratory Objectives ..........................................................................................23
3.
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ..................................................................................25
3.2
Duration and Study Completion Definition .............................................................26
3.3
Sites and Regions .....................................................................................................26
4.
STUDY POPULATION.........................................................................................................27
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................28
4.3
Reproductive Potential .............................................................................................29
4.3.1
Female Contraception............................................................................................29
4.4
Discontinuation of Subjects .....................................................................................30
4.4.1
Reasons for Discontinuation..................................................................................31
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................31
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
5.1
Prior Treatment ........................................................................................................32
5.2
Concomitant Treatment............................................................................................32
5.2.1
Permitted Treatment...............................................................................................32


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5.2.2
Prohibited Treatment .............................................................................................32
6.
INVESTIGATIONAL PRODUCT ........................................................................................34
6.1
Identity of Investigational Product...........................................................................34
6.1.1
Masking the Treatment Assignment ......................................................................34
6.1.2
Commercially Obtained Investigational Product...................................................34
6.2
Administration of Investigational Product(s)...........................................................34
6.2.1
Interactive Response Technology for Investigational Product Management ........34
6.2.2
Allocation of Subjects to Treatment ......................................................................34
6.2.3
Dosing....................................................................................................................35
6.2.4
Unmasking the Treatment Assignment..................................................................35
6.3
Labeling, Packaging, Storage, and Handling ...........................................................35
6.3.1
Labeling .................................................................................................................35
6.3.2
Packaging...............................................................................................................36
6.3.3
Storage ...................................................................................................................36
6.3.4
Special Handling....................................................................................................37
6.4
Drug Accountability.................................................................................................37
6.5
Subject Compliance..................................................................................................38
7.
STUDY PROCEDURES........................................................................................................39
7.1
Study Schedule.........................................................................................................39
7.1.1
Visit 1 (Day 1) .......................................................................................................39
7.1.2
Visit 2 (Day 3), Visit 3 (Day 6), and Visit 4 (Day 8) ............................................41
7.1.3
Visit 5 (End of Study or Early Termination) .........................................................41
7.1.4
Additional Care of Subjects after the Study ..........................................................41
7.2
Study Evaluations and Procedures ...........................................................................41
7.2.1
Demographic and Other Baseline Characteristics .................................................41
7.2.1.1
Demographics.........................................................................................41
7.2.1.2
Medication and Medical History............................................................41
7.2.1.3
AdenoPlus Test ......................................................................................42
7.2.2
Efficacy..................................................................................................................42
7.2.2.1
Clinical Resolution.................................................................................42
7.2.2.2
Adenoviral Eradication ..........................................................................42
7.2.3
Safety .....................................................................................................................42
7.2.3.1
Best Corrected Visual Acuity (BCVA)..................................................42
7.2.3.2
Slit Lamp Biomicroscopy.......................................................................43
7.2.3.3
Non-dilated/ Dilated Fundus Examination.............................................44
7.2.3.4
Adverse Event Collection.......................................................................44
7.2.3.5
Microbiology Laboratory Evaluations ...................................................44


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7.2.3.6
Pregnancy Test .......................................................................................45
7.2.3.7
Health-related Quality of Life Assessments...........................................45
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................46
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................46
8.1.1
Severity Categorization..........................................................................................46
8.1.2
Relationship Categorization...................................................................................47
8.1.3
Outcome Categorization ........................................................................................47
8.1.4
Symptoms of the Disease Under Study .................................................................47
8.1.5
Pregnancy...............................................................................................................48
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................48
8.2
Serious Adverse Event Procedures ..........................................................................49
8.2.1
Reference Safety Information................................................................................49
8.2.2
Reporting Procedures.............................................................................................49
8.2.3
Serious Adverse Event Definition .........................................................................50
8.2.4
Serious Adverse Event Collection Time Frame.....................................................50
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................50
8.2.6
Fatal Outcome........................................................................................................51
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................51
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................52
9.1
Data Collection.........................................................................................................52
9.2
Clinical Data Management.......................................................................................52
9.3
Data Handling Considerations..................................................................................52
9.4
Statistical Analysis Process......................................................................................52
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......53
9.6
Sample Size Calculation and Power Considerations................................................53
9.7
Study Population ......................................................................................................53
9.8
Efficacy Analyses.....................................................................................................54
9.8.1
Study Eye Designation...........................................................................................54
9.8.2
Primary Efficacy Endpoint ....................................................................................54
9.8.3
Key Secondary Efficacy Endpoints .......................................................................55
9.8.4
Secondary Efficacy Endpoints...............................................................................56
9.8.5
Exploratory Efficacy Endpoints.............................................................................57
9.9
Safety Analyses........................................................................................................57
9.10
Other Analyses .........................................................................................................58
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................59


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10.1
Sponsor’s Responsibilities .......................................................................................59
10.1.1 Good Clinical Practice Compliance.......................................................................59
10.1.2 Indemnity/Liability and Insurance.........................................................................59
10.1.3 Public Posting of Study Information......................................................................59
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................60
10.1.5 Study Suspension, Termination, and Completion..................................................60
10.2
Investigator’s Responsibilities .................................................................................60
10.2.1 Good Clinical Practice Compliance.......................................................................60
10.2.2 Protocol Adherence and Investigator Agreement..................................................61
10.2.3 Documentation and Retention of Records.............................................................61
10.2.3.1
Case Report Forms.................................................................................61
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................61
10.2.3.3
Audit/Inspection.....................................................................................62
10.2.3.4
Financial Disclosure...............................................................................62
10.3
Ethical Considerations..............................................................................................62
10.3.1 Informed Consent...................................................................................................62
10.3.2 Institutional Review Board or Ethics Committee..................................................63
10.4
Privacy and Confidentiality......................................................................................64
10.5
Study Results/Publication Policy .............................................................................64
11. REFERENCES .......................................................................................................................66
12. APPENDICES ........................................................................................................................68


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LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................18
Table 2  
Common Excluded Treatments and Associated Washout Periods................33
LIST OF FIGURES
Figure 1
SHP640-301 Study Design............................................................................25
LIST OF APPENDICES
Appendix 1
Protocol History.............................................................................................69
Appendix 2
Scales and Assessments.................................................................................75


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ABBREVIATIONS
AE
adverse event
BCVA
Best Corrected Visual Acuity
CC-IFA
cell culture-immunofluorescence assay
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
eCRF
electronic case report form
EC
ethics committee
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Conference on Harmonisation
IOP
intraocular pressure
IRB
Institutional Review Board
IRT
interactive response technology
ITT
Intent to Treat
mITT
Modified Intent to Treat
MRSA
methicillin-resistant Staphylococcus aureus
PVP-I
povidone-iodine
qPCR
quantitative polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment- emergent adverse event
US
United States


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STUDY SYNOPSIS
Protocol number: SHP640-301
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 100 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]) 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:

Adenovirus viral titer assessed by quantitative polymerase chain reaction (qPCR) at Visit 
3 (Day 6) and 4 (Day 8)

Adenoviral eradication as assessed by CC-IFA at Visits 4 (Day 8) and 5 (Day 12)

Clinical resolution  of adenoviral conjunctivitis at Visits 2 (Day 3), 4 (Day 8) and 5 (Day 
12) 

Individual clinical signs (bulbar conjunctival injection and watery conjunctival discharge) 
at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)


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
The global clinical score (sum of bulbar conjunctival injection and watery conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 6), 4 (Day 8) and 5 (Day 12). 

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)

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)

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 (Day 
8), and 5 (Day 12) 

To assess the status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected eye at 
baseline

To evaluate the safety and tolerability of SHP640 compared to 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 investigational product in each eye 4 times daily (with a minimum of 2 hours 
between doses) for 7 days.
Methodology:
Once screening and baseline assessments are complete and subjects are confirmed eligible to enroll in the study, 
subjects will be randomized, and investigational product will be administered on the same day (Day 1). The first 
dose will be administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 
times a day (QID) for 7 days. Additional visits will occur on Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), 
and Visit 5 (Day 12). The study will last up to 13 days. 
Inclusion and exclusion criteria: 
Inclusion Criteria:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions (by 
the parent(s), guardian, or legally authorized representative, if applicable).
2.
Ability to voluntarily provide written, signed, and dated (personally or via a parent(s), guardian, or 
legally-authorized representative(s) informed consent (and assent, if applicable) to participate in the 
study.
3.
Subjects of any age at Visit 1 (Note: subjects <3 months of age at Visit 1 must have been full-term, ie 


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≥37 weeks gestational age at birth).
4.
Have a positive AdenoPlus® test at Visit 1 in at least 1 eye.
5.
Have a clinical diagnosis of suspected adenoviral conjunctivitis in at least 1 eye (the same eye as the 
AdenoPlus positive eye) confirmed by the presence of the following minimal clinical signs and 
symptoms in that same eye:

Report presence of signs and/or symptoms of adenoviral conjunctivitis for ≤ 3 days prior to Visit 1

Bulbar conjunctival injection: a grade of ≥1 (mild) on a 0-4 Bulbar Conjunctival Injection Scale.

Watery conjunctival discharge: a grade of ≥1 (mild) on a 0-3 Watery Conjunctival Discharge Scale
6.
Be willing to discontinue contact lens wear for the duration of the study.
7.
Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better in each eye as measured using 
an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. BCVA will be assessed by an age 
appropriate method in accordance with the AAP Policy Statement for Visual System Assessment in 
Infants, Children, and Young Adults by Pediatricians (Donahue and Baker 2016; American Academy 
of Pediatrics 2016). The policy statement recommends formal vision screening can begin at 3 years of 
age. VA measurements for children under the age of 3 will be done at the discretion of the investigator. 
If not done, child should be able to fixate on and follow a moving object, except subjects <2 months of 
age who have not yet developed this ability. Subjects <2 months will be enrolled at the discretion of 
Investigator. 
8.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of non-childbearing potential. 
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1.
Current or recurrent disease that could affect the action, absorption, or disposition of the investigational 
product, or clinical or laboratory assessments, per investigator’s discretion.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may make the 
subject unlikely to fully complete the study, or any condition that presents undue risk from the 
investigational product or procedures.
3.
Have known or suspected intolerance or hypersensitivity to the investigational product, closely related 
compounds, or any of the stated ingredients. 
4.
Prior enrollment in a FST-100 or SHP640 clinical study.
5.
Subjects who are employees, or immediate family members of employees (who are directly related to 
study conduct), at the investigational site.
6.
Have a history of ocular surgical intervention within ≤6 months prior to Visit 1 or planned for the 
period of the study.
7.
Have a preplanned overnight hospitalization during the period of the study.
8.
Have presence of any intraocular, corneal, or conjunctival ocular inflammation (eg, uveitis, iritis, 
ulcerative keratitis, chronic blepharoconjunctivitis), other than adenoviral conjunctivitis.
9.
Have presence of corneal subepithelial infiltrates at Visit 1.
10. Have active or history of ocular herpes.
11. Have at enrollment or within ≤30 days of Visit 1, a clinical presentation more consistent with the 
diagnosis of ocular allergy, toxic conjunctivitis, or non-adenoviral ocular infection (eg, bacterial, 
fungal, acanthamoebal, other or parasitic).
12. Neonates or infants (ie. subjects less than 12 months of age) who have suspected or confirmed (based 
on the result of any test conducted prior to screening) conjunctivitis of gonococcal, chlamydial, 
herpetic or chemical origin.


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13. Neonates or infants (ie. subjects less than 12 months of age) whose birth mothers had any sexually 
transmitted disease within 1 month of delivery or any history of genital herpes.
14. Presence of nasolacrimal duct obstruction at Visit 1 (Day 1).
15. Presence of any significant ophthalmic condition (eg, Retinopathy of Prematurity, congenital cataract, 
congenital glaucoma) or other congenital disorder with ophthalmic involvement that could affect study 
variables.
16. Be a known intraocular pressure (IOP) steroid responder, have a known history of glaucoma, be a 
glaucoma suspect, or have a known history of an elevated IOP > 21 mmHg.
17. Have any known clinically significant optic nerve defects. 
18. Have a history of recurrent corneal erosion syndrome, either idiopathic or secondary to previous 
corneal trauma or dry eye syndrome; presence of corneal epithelial defect or any significant corneal 
opacity at Visit 1.
19. Presence of significant, active condition in the posterior segment which requires invasive treatment (eg, 
intravitreal treatment with VEGF inhibitors or corticosteroids) and may progress during the study 
participation period.
20. Have used any topical ocular or systemic anti-virals or antibiotics within ≤7 days of enrollment. 
21. Have used any topical ocular NSAIDs within ≤1 day of enrollment.
22. Have used any topical ophthalmic steroids in the last ≤14 days.
23. Have used any systemic corticosteroid agents within ≤14 days of Day 1. Stable (initiated ≥30 days 
prior to enrollment) use of inhaled and nasal corticosteroids is allowed, given no anticipated change in 
dose for the duration of the study. Topical dermal steroids are allowed except in the peri-ocular area.
24. Have used non-corticosteroid immunosuppressive agents within ≤14 days of Day 1.
25. Have used any topical ophthalmic products, including tear substitutes, and over-the-counter 
preparations such as lid scrubs, within 2 hours of Visit 1 and be unable to discontinue all topical 
ophthalmic products for the duration of the study. Use of hot or cold compresses is also not permitted 
during the study.
26. Have any significant ocular disease (eg, Sjogren's syndrome) or any uncontrolled systemic disease or 
debilitating disease (eg, cardiovascular disease, hypertension, sexually transmitted diseases/infections, 
diabetes or cystic fibrosis), that may affect the study parameters, per Investigator’s discretion.
27. Any known history of immunodeficiency disorder or known active conditions predisposing to 
immunodeficiency, such as human immunodeficiency virus, hepatitis B or C, evidence of  active 
hepatitis A (antihepatitis A virus immunoglobulin M), or organ or bone marrow transplantation.
28. Within 30 days prior to the first dose of investigational product:

Have used an investigational product or device, or

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study.
Maximum duration of subject involvement in the study:
Subject participation will last up to 13 days.
Screening, randomization and the first treatment administration will occur at Visit 1 (Day 1). 
Additional visits will occur on Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), and Visit 5 (Day 12). 
All follow-up procedures will be conducted at Visit 5 (Day 12).
Endpoints and statistical analysis:
Primary Efficacy Endpoint:
Clinical resolution status (defined as absence of bulbar conjunctival injection and watery conjunctival 
discharge) in the study eye at Visit 3 (Day 6) between SHP640 and placebo.
Key Secondary Efficacy Endpoints:


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Clinical resolution status 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.
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 signs score (bulbar conjunctival injection and watery conjunctival discharge) 
and change from baseline at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the  study eye

The global clinical score (as defined as the sum of bulbar conjunctival injection and watery 
conjunctival discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 6), 4 (Day 8) and 5 (Day 12) in the  study eye

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at Visits 2 (Day 3), 3 
(Day 6), 4 (Day 8) and 5 (Day 12) in the  study eye

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with neither injection 
nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the  study 
eye

The status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye at Visits 2 (Day 3), 
3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected eye at baseline

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8), and 5 
(Day 12) in the study eye
Safety Endpoints:

Best Corrected Visual Acuity (BCVA)

Slit Lamp Biomicroscopy 

Non-dilated/ Dilated Fundus Examination

Urine Pregnancy Testing (for females of childbearing potential)

Adverse Events (AEs)
Statistical Methods:
The analyses on primary, key secondary, secondary and exploratory efficacy endpoints will be performed on the 
mITT population (unless specified otherwise) and will be presented by treatment group. Additional sensitivity 
analyses may be conducted on the ITT population. Safety analysis will be conducted on the safety population.
For both efficacy and safety analyses, baseline is defined as the assessments taken at Visit 1 (Day 1).


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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 investigational product and have a positive CC-IFA adenovirus test at baseline in the study 
eye.
Designation of Study Eye:
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a score of at least 1 
for both watery conjunctival discharge and bulbar conjunctival redness at baseline (baseline is defined as the 
assessments taken at Visit 1 (Day 1):

For subjects with both eyes eligible and both with a positive CC-IFA result at baseline or both eyes 
eligible and both with a negative CC-IFA result at baseline, the study eye will be the eye with the 
highest global clinical score (sum of the scores for discharge and redness) at baseline. If both eyes have 
the same global clinical score at baseline, then the study eye will be the right eye.

For subjects with both eyes eligible with a positive CC-IFA result in one eye at baseline, the baseline 
CC-IFA positive eye will be the study eye.

For subjects with only one eligible eye, the eligible eye will be the study eye irrespective of its baseline 
CC-IFA status.
Primary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. There is a single 
primary comparison for the single primary endpoint. Therefore, no adjustment of multiplicity is needed for the 
hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 6) will be compared 
between the SHP640 and placebo group. The comparison will be based on the proportion of subjects with 
clinical resolution in the study eye at Visit 3 (Day 6) using Fisher’s Exact test at two sided 0.05 significance 
level. 
If subjects have missing clinical resolution status at Visit 3 (Day 6), then the last post-baseline observation will 
be carried forward (LOCF) for the determination of clinical resolution of the study eye. 
The null hypothesis to be tested is that there is no difference in proportion of subjects with clinical resolution in 
the study eye between SHP640 Ophthalmic Solution and Placebo with the alternative of the non-zero difference 
in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with two-sided Fisher’s Exact test at 5% 
level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical method(s) 
including other methods of imputation of missing data. Sensitivity analyses may be conducted in the ITT in 
addition to the mITT.
Key Secondary Efficacy Analyses:
All efficacy analyses will be performed on the mITT and presented by treatment groups. 
In order to maintain the study-wide Type I error at 5.0%, the primary and key secondary hypotheses will be 
tested sequentially using two-sided Fisher’s exact test according to the following sequence: 


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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 number of subjects (n), mean, median, standard deviation, minimum, maximum and 
confidence intervals.  Binary endpoints will be summarized by number of subjects (n), frequencies proportions 
and confidence intervals. Time to event endpoint will be summarized by Kaplan-Meier survival estimates.
Safety Analyses:
Safety data will be presented for the Safety Population by treatment group and overall. Adverse events will be 
coded using the Medical Dictionary for Regulatory Activities. The number of subjects and percentage with a 
treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated overall, by SOC, 
by preferred term, and by treatment group and overall. Treatment-emergent adverse events will be further 
summarized by severity and relationship to investigational product. Adverse events related to investigational 
product, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized and listed. Any AE that 
occurs after the first dose of investigational product instillation will be considered a TEAE.
Generally, TEAEs will be presented separated by whether or not the AE was an ocular or non-ocular AE.
BVCA, Slit Lamp Biomicroscopy, non-dilated/dilated fundus exam, and urine pregnancy test (for females of 
childbearing potential) will be descriptively summarized by treatment group and overall at each applicable visit.


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Study Schedule
Table 1
Schedule of Assessments
Procedure
(All ocular assessments and 
procedures performed bilaterally)
Visit 1
Screeninga & 
Baseline
(Day 1)
-1 day
Visit 2
(Day 3)
Visit 3
(Day 6)
Visit 4 
(Day 8)
Visit 5b
(Day 12)
+1 day
Informed consent/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
Ocular Discomfort Scale
X
X
X
X
X
Best corrected visual acuity
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
Bulbar conjunctival injection 
evaluation
X
X
X
X
X
Watery conjunctival discharge 
evaluation
X
X
X
X
X
AdenoPlus®  test
Xd
Conjunctival swab for viral culturee
Xm
Xf
Xf
Xf
Xf
Conjunctival swab for bacterial 
cultureg
X
Xfg
Xf
Non-dilated/ dilated fundus 
examinationh
X
X
Randomizationi
X
Dispense investigational product j
X
Instill investigational product
Xj
Xk
Xk
Collect investigational product
X
Xb
Compliance assessment
X
X
X
Xb
Drug accountability
X
Xb
Adverse events
Xl
X
X
X
X
Study completion
X


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Table 1
Schedule of Assessments
Procedure
(All ocular assessments and 
procedures performed bilaterally)
Visit 1
Screeninga & 
Baseline
(Day 1)
-1 day
Visit 2
(Day 3)
Visit 3
(Day 6)
Visit 4 
(Day 8)
Visit 5b
(Day 12)
+1 day
CC-IFA= cell culture-immunofluorescence assay; qPCR= quantitative polymerase chain reaction; 
a Informed consent and confirmation of inclusion/exclusion criteria can be conducted on Day -1; Inclusion/Exclusion 
must be re-confirmed on Day 1
b If investigational product is discontinued, regardless of the reason, all discontinued subjects should proceed to Visit 
5 whenever possible. Subjects that discontinue the study and proceed to Visit 5 should perform all Visit 5 
assessments as well as drug return, compliance and accountability.
c Women of childbearing potential, prior to enrollment and at exit from the study.
d If not previously conducted within 24 hours of Visit 1 (Day 1)
e One swab sample from inferior conjunctival cul-de-sac of each eye will be collected for all viral testing. If the CC-
IFA test is positive, qPCR will be performed. Adenoviral serotyping will be conducted at baseline only.
f Conjunctival swab samples MUST be taken at least 12 hours after the last dose of investigational product at Visits 
2, 3, 4 and ET, if applicable.
g One swab sample from each conjunctival cul-de-sac will be collected for all bacterial testing.
h If a non-dilated fundus exam is not feasible, a dilated examination should be conducted. For each subject, the exam 
should be conducted the same way (either non-dilated or dilated) at both Visit 1 and Visit 5 (or ET).    
i All assessments, randomization, and investigational product instillation on Day 1 must take place with sufficient 
time to allow all 4 Day 1 doses (with a minimum of 2 hours between doses)
.j The investigational product bottle should be shaken well prior to use at each dosing. The first dose will be 
administered by site staff on Day 1, and thereafter subjects will administer 1 drop in each eye 4 times a day for 7 
days.
k Investigational product instillation should only be performed in-office if it is necessary.
l Monitoring for adverse events will begin after informed consent is obtained.
m For subjects <2 months of age testing will be conducted using the same sample for chlamydia and gonorrhea  
detection.


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Conjunctivitis affects all populations worldwide of all ages and social strata, irrespective of 
gender. Within infectious conjunctivitis, viral etiology may account for up to 80% of all cases in 
adults and bacterial conjunctivitis is the second most common cause of infectious conjunctivitis 
overall. Infectious conjunctivitis represents a serious public health issue due to a risk of highly 
infectious epidemics, lost productivity, significant patient discomfort, and in some cases 
permanent visual compromise from long-term, immune-mediated sequelae (Ford et al., 1987; 
Nauheim et al., 1990; Gordon et al., 1993; Pelletier et al., 2009; Capriotti et al., 2010).
Adenoviruses, unlike bacteria, are not part of the normal flora of the ocular surface and their 
presence is indicative of an infection (Cambon and Pollard, 1959; Willamson et al., 1975; 
Vastine et al., 1977; Gigliotti et al., 1981; Kaneko et al., 2008). It is the most reported cause of 
viral conjunctivitis in up to 75% of cases (Wilkins et al., 2011). Adenoviral conjunctivitis is 
typically spread through direct contact between the eye and hands that are contaminated with the 
virus via contact with infected eye discharge, fecal matter, or respiratory discharge (CDC, 2010). 
Given the highly transmittable nature of the disease, it is not surprising that it is observed to be 
most prevalent in densely populated, overcrowded areas, or in the presence of poor hygiene, or 
both (Capriotti et al., 2010).
Adenoviral conjunctivitis typically lasts 14-21 days (Wilkins et al., 2011). The onset is usually 
rapid and the infection often spreads from one eye to the other (AAO Cornea/External Disease 
PPP Panel, 2013). 
Currently, there are no approved treatments for adenoviral conjunctivitis; therapeutic options are 
limited to supportive therapies and palliative measures such as cold compresses, artificial tears, 
and topical antihistamines (AAO Cornea/External Disease PPP Panel, 2013). This Phase 3 study 
is being conducted to evaluate the clinical efficacy and safety of SHP640 for the treatment of 
adenoviral conjunctivitis.
1.2
Product Background and Clinical Information
SHP640, a novel topical ophthalmic suspension, is currently under development for the treatment 
of infectious conjunctivitis (adenoviral and bacterial).
SHP640 contains 2 active ingredients: povidone-iodine (PVP-I) and dexamethasone. PVP-I is a 
multivalent broad-spectrum local antiseptic with bactericidal and fungicidal properties. The 
effect on vegetative cells of various bacteria and fungi is due to the liberation of free iodine from 
the complex. It is effective against many viruses, protozoa, yeasts, cysts, and spores (Betadine, 
2004). Dexamethasone is a corticosteroid routinely used as a topical ophthalmic suspension for 
the treatment of ocular inflammation. It suppresses the inflammatory response to a variety of 
causes of inflammation (Maxidex, 2007). Both components are currently approved for use in 
other indications (at similar or higher concentrations) and have been shown to be safe and 
efficacious for use on the ocular surface in humans. The combination of PVP-I and 


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dexamethasone has been shown to rapidly kill common ocular pathogens, including viruses, 
gram-positive bacteria (including MRSA), and gram-negative bacteria (Pelletier et al., 2011).
Always refer to the latest version of the SHP640 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy and safety of SHP640. 


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The clinical presentation of conjunctivitis is often nonspecific and differential diagnosis of 
different types of conjunctivitis can be challenging (Azari and Barney, 2013; O'Brien et al., 
2009). Diagnostic testing to differentiate the underlying cause of infection is rarely performed in 
a clinical setting; misdiagnosis can occur in up to 50% of cases, which often results in improper 
antibiotic treatment (Visscher et al., 2009). Incorrect treatment can not only increase healthcare 
costs from unnecessary antibiotic prescriptions and repeat office visits, but can also pose serious 
risks for people with certain viral and bacterial variants (eg, herpes simplex or methicillin-
resistant Staphylococcus aureus [MRSA]). In addition, there is also a risk of overuse and misuse 
of antibiotics, which are ineffective in the treatment of viral infections (Statham et al., 2008). 
Currently there is no approved medication for the treatment of adenoviral conjunctivitis. An 
unmet medical need therefore exists for a safe and efficacious treatment that addresses both 
bacterial and adenoviral conjunctivitis, two of the leading causes of acute infectious 
conjunctivitis.
By combining PVP-I, a potent topical antiseptic with proven antiviral and antibacterial activity, 
with dexamethasone, a topical steroid, SHP640 will enable the treatment of both the infectious 
and inflammatory components of adenoviral and bacterial conjunctivitis.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of SHP640 based on clinical 
resolution (defined as absence of bulbar conjunctival injection and watery conjunctival 
discharge) compared with placebo in the treatment of subjects with adenoviral conjunctivitis in 
the study eye at Visit 3 (Day 6). 
2.2.2
Key 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]) 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).


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Adenoviral eradication is defined in Section 7.2.2.
2.2.3
Secondary Objectives
Secondary objectives of this study are as follows:

To evaluate the effect of treatment in the study eye, for the following endpoints:

Adenovirus viral titer assessed by quantitative polymerase chain reaction (qPCR) at 
Visit 3 (Day 6) and 4 (Day 8)

Adenoviral eradication as assessed by CC-IFA at Visits 4 (Day 8) and 5 (Day 12)

Clinical resolution of adenoviral conjunctivitis at Visits 2 (Day 3), 4 (Day 8) and 5 (Day 
12)

Individual clinical signs (bulbar conjunctival injection and watery conjunctival 
discharge) at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)

The global clinical score (sum of bulbar conjunctival injection and watery conjunctival 
discharge) and change from baseline in the global clinical score at Visits 2 (Day 3), 3 
(Day 6), 4 (Day 8) and 5 (Day 12). 

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)

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)

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 
(Day 8), and 5 (Day 12) 

To assess the status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye
at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 infected eye at 
baseline

To evaluate the safety and tolerability of SHP640, compared to PVP-I and placebo in the 
treatment of subjects with adenoviral conjunctivitis
2.2.4
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 will be randomized into the study at Visit 1 (Day 1). Subjects will 
be randomized 2:2:1 to receive either SHP640, PVP-I, or placebo within each stratum. 
Randomization will be stratified by age to maintain the randomization ratio among subjects < 6 
years, 6 to <18 years and subjects ≥18 years.
Multiple subjects from the same household will be eligible to participate in the study. Subjects 
from the same household will be assigned to the same treatment group to which the first enrolled 
subject in the household was randomized in order to prevent treatment administration errors or 
potential treatment unmasking. Dynamic balanced randomization will be used in this study to 
maintain the randomization ratio within each stratum. 
Once screening and baseline assessments are complete and subjects are confirmed eligible to 
enroll in the study, subjects will be randomized, and investigational product will be administered 
on the same day (Day 1). The first dose will be administered by site staff on Day 1, and 
thereafter subjects will administer 1 drop in each eye 4 times a day (QID) for 7 days. Additional 
visits will occur on Visit 2 (Day 3), Visit 3 (Day 6), Visit 4 (Day 8), and Visit 5 (Day 12). All 
follow-up procedures will be conducted at Visit 5 (Day 12). The study will last up to 13 days. 
Figure 1 provides the study design.
Figure 1
SHP640-301 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 100 sites across North America, South America, 
Asia/Pacific, and Europe.


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


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


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


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


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


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


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Table 2  
Common Excluded Treatments and Associated Washout Periods
Minimum Time Prior to First 
Dose
Notes
Treatment
30 
days 
14 
days
7 
days
1 
day
2 
hours
Topical ocular NSAIDs
X
Topical ocular or systemic anti-virals
X
Topical ophthalmic steroids
X
Systemic corticosteroid agents
X
Stable use of inhaled or nasal 
corticosteroids
X
Allowed ≥30 days if no 
anticipated dose changes 
during the study
Non-corticosteroid 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, IMP returns, accountability of 
IMP, and emergency unmasking.
6.2.2
Allocation of Subjects to Treatment 
This is a double-masked, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment is 
automatically assigned by the IRT.
Randomization will be stratified by age to maintain the randomization ratio among subjects < 6 
years, 6 to <18 years and subjects ≥18 years.  Subjects will be randomly assigned to receive 
SHP640, PVP-I 0.6%, or placebo based on a 2:2:1 ratio [SHP640: PVP-I 0.6%: placebo] within 
the randomization strata.


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


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


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


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


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


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


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7.1.2
Visit 2 (Day 3), Visit 3 (Day 6), and Visit 4 (Day 8)
Visit 2 (Day 3), Visit 3 (Day 6), and Visit 4 (Day 8) assessments will be performed as outlined in 
Table 1 and as described in the Study Operations Manual. Assessments should be performed in 
descending order as listed.
Subject compliance will be verified verbally during study visits. In cases of non-compliance the 
investigator should determine if the medical monitor must be contacted for consultation. 
Subjects should not instill investigational product within 12 hours of scheduled Study Visits. To 
ensure this, subjects should be reminded to not dose the morning of Visits 2, 3 and 4. 
Investigational product instillation should only be performed in-office if it is necessary, and 
should be done once all other assessments are completed. Subjects who instill investigational 
product less than 12 hours before study visits will be recorded as protocol deviations.
7.1.3
Visit 5 (End of Study or Early Termination)
Safety follow-up will be conducted at Visit 5 (the end of study visit). Visit 5 (Day 12) 
assessments will be performed as outlined in Table 1. Assessments should be performed in 
descending order as listed.
Subjects who discontinue the study and proceed to Visit 5 for early termination should have 
investigational product collected, a compliance assessment, and drug accountability assessed at 
their final visit.
All AEs and SAEs that are not resolved at the time of Visit 5 or early termination will be 
followed to closure (see Section 8.1).
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
7.2.1.1
Demographics
Demographic information will be collected at Visit 1. Date of Birth (where permitted), Age, Sex, 
Race, and Ethnicity will be recorded.
7.2.1.2
Medication and Medical History
MEDICATION HISTORY
Refer to Section 5 for full details on collection of prior treatment.
The investigator will categorize treatments as ocular (specified as left eye, right eye or both eyes) 
or non-ocular based on the indication for use.  Prior treatment information must be recorded on 
the appropriate CRF page.  


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MEDICAL HISTORY
The site must record all clinically or medically relevant information regardless of how much time 
has elapsed since the date of any diagnosis. Medical history will be classified as ocular (specified 
as left eye, right eye or both eyes) or non-ocular by the investigator. History should include, but 
is not limited to: 

History of ocular diseases/conditions. 

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, and any other non-ocular diseases/underlying conditions within 
the past year prior to the Screening Visit (Visit 1).
7.2.1.3
AdenoPlus Test
The AdenoPlus test will be performed at Visit 1 as outlined in Table 1. A positive result in at 
least one eye is required for enrollment in this study.
The AdenoPlus test is an in-office test that allows for the detection of adenoviral antigens 
directly from human eye fluid. A small tear sample is transferred onto the AdenoPlus test, which 
confirms the presence of adenovirus and the viral form of conjunctivitis. 
Please refer to the Operations Manual for a detailed description of the AdenoPlus Test and 
administration.
7.2.2
Efficacy
7.2.2.1
Clinical Resolution
Clinical resolution of adenoviral conjunctivitis is defined as the absence (score = 0) of bulbar 
conjunctival injection and watery conjunctival discharge in the study eye. Bulbar Conjunctival 
Injection will be assessed based on a 0-4 scale which uses pictures from the Validated Bulbar 
Redness (VBR) Scale and Watery Conjunctival Discharge will be assessed based on a 0-3 scale. 
Details of the Bulbar Conjunctival Injection and Watery Conjunctival Discharge scales are 
located in the study Operations Manual.
7.2.2.2
Adenoviral Eradication
Adenoviral eradication for an eye is defined as negative CC-IFA in that eye.  CC-IFA for each 
eye will be conducted using conjunctival swab samples collected at each visit. See the 
Laboratory Manual for further details.
7.2.3
Safety
Safety assessments will be performed in both eyes.
7.2.3.1
Best Corrected Visual Acuity (BCVA)
The BCVA will be performed prior to slit lamp examination during the study as outlined in 
Table 1.


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The complete instructions for performing the BCVA are in the Operations Manual. Changes in 
VA will be assessed for clinical significance. Clinically significant changes should be recorded 
in the source and on the eCRF as an AE.
For subjects who are too young to use an ETDRS chart, use an age-appropriate measurement 
method in accordance with the AAP Policy Statement for Visual System Assessment in Infants, 
Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American Academy of 
Pediatrics, 2016; located in the Operations Manual). The policy statement recommends formal 
vision screening can begin at 3 years of age. VA measurements for children under the age of 3 
will be done at the discretion of the investigator. If not done, child should be able to fixate on 
and follow a moving object. This is not a requirement in subjects <2 months of age since the 
ability does not develop until about 2 months of age. However, if an infant <2 months of age is 
able to fix and follow, it should be recorded. The enrollment of subjects <2 months of age will be 
based on subject qualifying all other eligibility criteria and Investigator discretion.
VA is to be measured using the same method at all visits in the same subject.
7.2.3.2
Slit Lamp Biomicroscopy
Slit lamp biomicroscopy (or hand held slit lamp) will be performed during the study as outlined 
in Table 1. Magnification of the slit lamp will be consistent with standard clinical practice. The 
subject will be seated.
Observations will be graded as Normal or Abnormal. Abnormal findings will be described, and 
clinically significant abnormalities should be recorded in the source and on the electronic CRF 
(eCRF) (in Medical History at Screening; any changes from the screening visit may be recorded 
as adverse events by the investigator). Please note the investigator may use his/her discretion to 
determine whether Not Clinically Significant (NCS) and disease progression should be 
considered AEs). The following will be examined at each visit: 

Lids 

Conjunctiva 

Cornea

Anterior Chamber

Iris

Lens
For infants and young children, if the above exams cannot be performed with a slit lamp or a 
hand held slit lamp, an external examination is to be conducted in accordance with American 
Academy of Pediatrics (AAP) Policy Statement for Visual System Assessment in Infants, 
Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American Academy of 
Pediatrics, 2016; located in the Operations Manual). The examination of lens in these subjects 
should be conducted at Visit 1 and Visit 5 (or ET visit) and graded based on the external 


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examination and red reflex exam (Section 7.2.3.3). All other structures listed above will be 
examined and graded at all visits based on the external examination. Observations will be graded 
as Normal or Abnormal. Abnormal findings will be described.
7.2.3.3
Non-dilated/ Dilated Fundus Examination
Fundus examination must be conducted after BCVA, Slit Lamp Biomicroscopy and conjunctival 
swab for adenoviral and bacterial culture has been collected. 
A non-dilated fundus examination will be performed in all subjects with the exception of infants 
and uncooperative small children during the study as outlined in Table 1.
Observations will be graded as Normal or Abnormal. Abnormal findings will be described.
The following will be examined:

Vitreous

Optic Nerve

Macula
Clinically significant changes should be recorded in the source and on the eCRF as an AE.
If a non-dilated fundus exam is attempted and is not feasible, dilated fundus exam should be 
conducted. The test should be conducted the same way (either dilated or non-dilated) at both 
Visit 1 and Visit 5 (or ET).
For infants and small children in whom a fundus examination cannot be done, a red reflex exam 
will be conducted in accordance with AAP Policy Statement for Visual System Assessment in 
Infants, Children, and Young Adults by Pediatricians (Donahue and Baker, 2016; American 
Academy of Pediatrics, 2016; located in the Operations Manual). Observations will be graded as 
Normal or Abnormal. Abnormal findings will be described. The red reflex should be normal 
(present and symmetrical for both eyes) at the screening/ baseline visit.
7.2.3.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.) Any AE that occurs after the first dose of 
investigational product instillation will be considered a TEAE.
Adverse events may also be determined by the investigator during study examinations as 
mentioned in previous sections.
7.2.3.5
Microbiology Laboratory Evaluations
All laboratory assays will be performed according to the laboratory’s normal procedures. 


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All bioanalytical assays for the study will be validated following FDA/ICH guidelines, based on 
the method's intended use. The lab will only receive sample ID numbers and collection dates, the 
lab results will then be transferred to the central lab for data analysis. The lab will not receive 
any information on subject treatment assignment.
The following laboratory assessments will be performed: 

Cell Culture 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 each eye will be taken from inferior conjunctival cul-de-sac at all study 
visits for adenoviral testing. For neonates and infants <2 months of age, PCR testing for presence 
of chlamydia and gonorrhea at baseline will also be conducted using the baseline visit sample.
7.2.3.6
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 three items: pain, itching, and 
foreign body sensation. All items will be evaluated using a 0-10 scale. A separate scale will be 
administered for children less than 8 years of age (binary ocular discomfort). Please see the 
Operations Manual for a detailed description of this assessment.


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


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


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


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


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


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


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


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All statistical analyses will be performed after the database is locked and unmasked.
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513) Version 
9.2 or higher. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis, adaptive design, or data monitoring committee (DMC) in 
this study.
9.6
Sample Size Calculation and Power Considerations
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 with missing clinical resolution status at 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 investigational product 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, secondary and exploratory efficacy endpoints will be 
performed on the mITT population (unless specified otherwise) and will be presented by 
treatment group. 
Additional sensitivity analyses may be conducted in the ITT population.
Efficacy data collected at Baseline (Visit 1 [Day 1]) will be used as the baseline for both efficacy 
and safety analyses. For both efficacy and safety analyses, baseline is defined as the assessments 
taken at Visit 1 (Day 1).
9.8.1
Study Eye Designation
The study eye for analyses will be defined as follows, where an eligible eye is an eye with a 
score of at least 1 for both watery conjunctival discharge and bulbar conjunctival redness at 
baseline (baseline is defined as the assessments taken at Visit 1 [Day 1]):

For subjects with both eyes eligible and both with a positive CC-IFA result at baseline or 
both eyes eligible and both with a negative CC-IFA result at baseline, the study eye will be 
the eye with the highest global clinical score (sum of the scores for discharge and redness) at 
baseline. If both eyes have the same global clinical score at baseline, then the study eye will 
be the right eye. 

For subjects with both eyes eligible with a positive CC-IFA result in one eye at baseline, the 
baseline CC-IFA positive eye will be the study eye. 

For subjects with only one eligible eye, the eligible eye will be the study eye irrespective of 
its baseline CC-IFA status.
9.8.2
Primary Efficacy Endpoint
The primary efficacy endpoint is clinical resolution status (defined as absence [ie a score of 0] of 
bulbar conjunctival injection and watery conjunctival discharge) in the study eye at Visit 3 (Day 
6) between SHP640 and placebo.
All efficacy analyses will be performed on the mITT and presented by treatment groups. There is 
a single primary comparison for the single primary endpoint. Therefore, no adjustment of 
multiplicity is needed for the hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at Visit 3 (Day 6) will be 
compared between the SHP640 and placebo group. The comparison will be based on the 
proportion of subjects with clinical resolution in the study eye at Visit 3 (Day 6) using Fisher’s 
Exact test at two sided 0.05 significance level. 
If subjects have missing clinical resolution status at Visit 3 (Day 6), then the last post-baseline 
observation will be carried forward (LOCF) for the determination of clinical resolution of the 
study eye. 


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The null hypothesis to be tested is that there is no difference in proportion of subjects with 
clinical resolution in the study eye between SHP640 Ophthalmic Solution and Placebo with the 
alternative of the non-zero difference in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with two-sided Fisher’s 
Exact test at 5% level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using additional statistical 
method(s) including other methods of imputation of missing data. Sensitivity analyses may be 
conducted in the ITT in addition to the mITT. In addition, descriptive statistics will be generated 
for the primary efficacy endpoint by treatment within the overall pediatric population (ie birth to 
18 years) and within each pediatric age stratum (birth to <6 years and 6 to <18 years) in mITT. A 
detailed plan for primary analysis including additional sensitivity analyses will be described in 
the Statistical Analysis Plan (SAP).
9.8.3
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints of this study are clinical resolution status 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.
All efficacy analyses will be performed on the mITT and presented by treatment groups. In order 
to maintain the study-wide Type I error at 5.0%, the primary and key secondary hypotheses will 
be tested sequentially using two-sided Fisher’s exact test according to the following sequence: 


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Sensitivity analyses will also be done on key secondary efficacy endpoints using similar methods 
as described above. In addition, descriptive statistics will be generated for the key secondary 
efficacy endpoint by treatment within the overall pediatric population (ie birth to 18 years) and 
within each pediatric age stratum (birth to < 6 years and 6 to <18 years) in mITT. Details on the 
analyses will be described in the Statistical Analysis Plan (SAP).
9.8.4
Secondary Efficacy Endpoints
All secondary efficacy analyses will be performed on the mITT and presented by treatment 
group.  No hypothesis testing is planned for the secondary efficacy endpoints.  All secondary 
efficacy endpoint will be summarized by treatment groups using descriptive statistics at each 
assessment visit.  Continuous endpoints will be summarized by number of subjects (n), mean, 
median, standard deviation, minimum, maximum and confidence intervals.  Binary endpoints 
will be summarized by number of subjects (n), frequencies, proportions and confidence intervals.
Time to event endpoint will be summarized by Kaplan-Meier survival estimates.
Secondary efficacy endpoints are defined as follows:

Absolute and change from baseline in adenovirus viral titer as assessed by qPCR at 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 signs score (bulbar conjunctival injection and watery conjunctival 
discharge) and change from baseline at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12)
in the study eye


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
The global clinical score (defined as the sum of bulbar conjunctival injection and 
watery conjunctival discharge) and change from baseline in the global clinical score 
at Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the study eye

Modified clinical resolution status, defined as a global clinical score of 0 or 1, at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) in the study eye

Expanded clinical resolution status, defined as a global clinical score of 0, 1, or 2 with 
neither injection nor discharge having a score of 2, at Visits 2 (Day 3), 3 (Day 6), 4 
(Day 8) and 5 (Day 12) in the study eye

The status of cross-over infection (as assessed by CC-IFA) to a subject’s fellow eye at 
Visits 2 (Day 3), 3 (Day 6), 4 (Day 8) and 5 (Day 12) for subjects with only 1 
infected eye at baseline

Time to clinical resolution based upon assessments at Visits 2 (Day 3), 3 (Day 6), 4 
(Day 8), and 5 (Day 12) in the study eye
9.8.5
Exploratory Efficacy Endpoints
9.9
Safety Analyses
Safety data will be presented for the Safety Population by treatment group and overall.
Safety data collected at baseline (Visit 1 / Day 1) will be used as the baseline value for safety 
analysis.
Adverse events, including those suggestive of any local tolerability issues, will be coded using 
the Medical Dictionary for Regulatory Activities. The number of subjects and percentage with a 
treatment-emergent adverse event (TEAE) as well as the number of TEAEs will be calculated 
overall, by SOC, by preferred term, and by treatment group and overall. Treatment-emergent 
adverse events will be further summarized by severity and relationship to investigational 
product. Adverse events related to investigational product, AEs leading to withdrawal, SAEs, 
and deaths will be similarly summarized and listed.


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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 and overall 
at each applicable visit:

Best Corrected Visual Acuity (BCVA)

Slit Lamp Biomicroscopy

Lids 

Conjunctiva 

Cornea 

Anterior Chamber 

Iris

Lens 

Non-dilated/ Dilated Fundus Examination

Vitreous 

Optic Nerve 

Macula 

Urine Pregnancy Testing (for females of childbearing potential)
9.10
Other Analyses
No other analyses are planned in this study.


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


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


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


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


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


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


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


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11.
REFERENCES
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2013 - Cornea/External Disease Preferred Practice Pattern Guidelines. Conjunctivitis. 
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American Academy of Pediatrics 2016. Visual system assessment in infants, children, and young 
adults by pediatricians. Pediatrics, 137, 28-30.
Azari, A. A. & Barney, N. P. 2013. Conjunctivitis: a systematic review of diagnosis and 
treatment. Jama, 310, 1721-9.
Betadine 2004. Betadine Prescribing Information.
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 
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CDC. 2010. Conjunctivitis (pink eye) [Online]. Centers for Disease Control and Prevention. 
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Donahue, S. P. & Baker, C. N. 2016. Procedures for the Evaluation of the Visual System by 
Pediatricians. Pediatrics, 137.
Ford, E., Nelson, K. E. & Warren, D. 1987. Epidemiology of epidemic keratoconjunctivitis. 
Epidemiol Rev, 9, 244-61.
Gigliotti, F., Williams, W. T., Hayden, F. G., Hendley, J. O., Benjamin, J., Dickens, M., 
Gleason, C., Perriello, V. A. & Wood, J. 1981. Etiology of acute conjunctivitis in 
children. J Pediatr, 98, 531-6.
Gordon, Y. J., Gordon, R. Y., Romanowski, E. & Araullo-Cruz, T. P. 1993. Prolonged recovery 
of desiccated adenoviral serotypes 5, 8, and 19 from plastic and metal surfaces in vitro. 
Ophthalmology, 100, 1835-9; discussion 1839-40.
Kaneko, H., Maruko, I., Iida, T., Ohguchi, T., Aoki, K., Ohno, S. & Suzutani, T. 2008. The 
possibility of human adenovirus detection from the conjunctiva in asymptomatic cases 
during nosocomial infection. Cornea, 27, 527-30.
Maxidex 2007. Maxidex Prescribing Information.
Nauheim, R. C., Romanowski, E. G., Araullo-Cruz, T., Kowalski, R. P., Turgeon, P. W., Stopak, 
S. S. & Gordon, Y. J. 1990. Prolonged recoverability of desiccated adenovirus type 19 
from various surfaces. Ophthalmology, 97, 1450-3.
O'Brien, T. P., Jeng, B. H., McDonald, M. & Raizman, M. B. 2009. Acute conjunctivitis: truth 
and misconceptions. Curr Med Res Opin, 25, 1953-61.
Pelletier, J. S., Miller, D., Liang, B. & Capriotti, J. A. 2011. In vitro efficacy of a povidone-
iodine 0.4% and dexamethasone 0.1% suspension against ocular pathogens. J Cataract 
Refract Surg, 37, 763-6.
Pelletier, J. S., Stewart, K., Trattler, W., Ritterband, D. C., Braverman, S., Samson, C. M., Liang, 
B. & Capriotti, J. A. 2009. A combination povidone-iodine 0.4%/dexamethasone 0.1% 
ophthalmic suspension in the treatment of adenoviral conjunctivitis. Adv Ther, 26, 776-
83.
Pocock, S. J. & Simon, R. 1975. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 31, 103-15.


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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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The number of planned study sites was updated for accuracy.
Synopsis
Section 3.3
Inclusion Criteria 3 was updated to remove lower age limit.
Inclusion Criteria 7 was expanded as follows:
Have a Best Corrected Visual Acuity (BCVA) of 0.60 logMAR or better 
in each eye as measured using an Early Treatment Diabetic Retinopathy 
Study (ETDRS) chart. BCVA will be assessed by an age appropriate 
method in accordance with the AAP Policy Statement for Visual System 
Assessment in Infants, Children, and Young Adults by Pediatricians
(Donahue and Baker 2016; American Academy of Pediatrics 2016). The 
policy statement recommends formal vision screening can begin at 3 years 
of age. VA measurements for children under the age of 3 will be done at 
the discretion of the investigator. If not done, child should be able to 
fixate on and follow a moving object, except subjects <2 months of age 
who have not yet developed this ability. Subjects <2 months will be 
enrolled at the discretion of Investigator.
Synopsis
Section 4.1
Exclusion criteria were modified and renumbered per the discretion of the 
study team prior to subject enrollment (the Exclusion Criteria numbers 
below reflect the current document unless noted otherwise):

Previous Exclusion Criteria 6 was removed as there is no longer 
a prespecified household cap.

chronic blepharoconjunctivitis was added to Exclusion Criteria 8

Exclusion Criteria 12 and 13 were modified to reflect the 
removal of the lower age limit.

Exclusion Criteria 11, 14, and 15 were added.

Previous Exclusion Criteria 16 was removed (History of corneal 
transplant in either eye).

Corneal epithelial defect was added to Exclusion Criteria 18.

Antibiotics were added to Exclusion Criteria 20.

Exclusion Criteria 22 was modified as follows: Have used any 
topical ophthalmic steroids in the last ≤14 30 days.

Restriction of inhaled systemic corticosteroid agents was 
removed from Exclusion Criteria 23.

Exclusion Criteria 24 was updated to clarify that non-
corticosteroid immunosuppressive agents within ≤14 days of Day 
1

Exclusion Criteria 25 was modified to note that use of hot or cold 
compresses is also not permitted during the study.

Previous Exclusion Criteria 25 (Have any autoimmune disease.) 
was removed.
Synopsis
Section 4.2
Contraception text modified. Intrauterine hormone-releasing systems plus 
condoms was added as an acceptable form of contraception and the note 
related to subjects that become sexually active during the study was 
removed due to the short study duration.
Section 4.3.1
Discontinuation language updated as follows:
A subject may withdraw from the study at any time for any reason without 
prejudice to their future medical care by the physician or at the institution. 
The investigator or sponsor may withdraw the subject at any time (eg, if in 
the judgment of the investigator, treatment with an alternate therapy is in 
the best interest of subject for safety reasons there is no clinical 
Section 4.4


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improvement or worsening to an extent that it would be in the best interest 
of the subject to be treated with an alternate therapy for safety reasons). 
The investigator is encouraged to discuss withdrawal of a subject from 
investigational product with the medical monitor when possible if 
necessary.
Table 2 “Common Excluded Treatments and Associated Washout 
Periods” was updated.
Section 5.2.2
Emergency unmasking added to list of IRT vendor responsibilities.
Section 6.2.1
Pocock and Simon 1975 reference added for dynamic balanced 
randomization. 
Noted that randomization will be done centrally.
Section 6.2.2
Storage requirement language moved to correct location from Section 
6.2.3 to Section 6.3.3.
Section 6.2.3 
Section 6.3.3
Treatment unmasking language was updated.
Section 6.2.4
Specific treatment compliance range was removed.
Section 6.5
Section 7.1.2
Order of assessments and the details of study procedures in Visit 1 were
updated for accuracy.
Section 7.1.1
Noted that subjects should be reminded to not dose the morning of Visits 
2, 3 and 4.
Section 7.1.2
Clarified that demographic information will be collected at Visit 1. Date 
of Birth (where permitted), Age, Sex, Race, and Ethnicity will be recorded
Section 7.2.1.1
Updated to note that the site must record all clinically or medically 
relevant information regardless of how much time has elapsed since the 
date of any diagnosis. Previous protocol assigned this responsibility 
specifically to the investigator.
Clarified that Medical history will be classified as ocular (specified as left 
eye, right eye or both eyes).
Section 7.2.1.2
It was noted that a positive AdenoPlus result in at least one eye is required 
for enrollment in this study.
Section 7.2.1.3
Definition of adenoviral eradication updated to be non-specific to the 
study eye:
Adenoviral eradication for an eye is defined as negative CC-IFA in that
the study eye. CC-IFA for each eye will be conducted using conjunctival 
swab samples collected at each visit. from the study eyes. 
This change is also reflected in wording of the second key secondary 
objective.
Section 7.2.2.2
Section 2.2.2
Synopsis
Best Corrected Visual Acuity subsection was moved to indicate order of 
procedures.
Section 7.2.3.1
Clarified that the following will be examined at each visit via slit lamp 
biomicroscopy: 

Lids 

Conjunctiva 

Cornea
Synopsis
Section 7.2.3.2


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
Anterior Chamber

Iris

Lens
Added additional details for process for infants and children. For infants 
and young children, if the above exams cannot be performed with a slit 
lamp or a hand held slit lamp, an external examination is to be conducted 
in accordance with American Academy of Pediatrics (AAP) Policy 
Statement for Visual System Assessment in Infants, Children, and Young 
Adults by Pediatricians (Donahue and Baker 2016; American Academy of 
Pediatrics 2016; located in the Operations Manual). The examination of 
lens in these subjects should be conducted at Visit 1 and Visit 5 (or ET 
visit) and graded based on the external examination and red reflex exam 
(section 7.2.3.3). All other structures listed above will be examined and 
graded at all visits based on the external examination. Observations will 
be graded as Normal or Abnormal. Abnormal findings will be described.
Updated to indicate the fundus examination must be conducted after 
BCVA, Slit Lamp Biomicroscopy and conjunctival swab for adenoviral 
and bacterial culture has been collected. Clarified  that a non-dilated or 
dilated fundus examination may conducted, and that the following will be 
evaluated: Vitreous, Optic Nerve, and Macula.
Clarified that a dilated fundus examination should be conducted if a non-
dilated fundus examination is not feasible (for instance, in young children 
and infants).
Updated to indicate that for infants and small children in whom a fundus 
examination cannot be done, a red reflex exam will be conducted in 
accordance with AAP Policy Statement for Visual System Assessment in 
Infants, Children, and Young Adults by Pediatricians (Donahue and Baker 
2016; American Academy of Pediatrics 2016; located in the Operations 
Manual). Observations will be graded as Normal or Abnormal. Abnormal 
findings will be described. The red reflex should be normal (present and 
symmetrical for both eyes) at the screening/ baseline visit.
Synopsis
Section 7.2.3.3
Update to indicate that two swab samples  (one for adenoviral and one for 
bacterial) from each eye will be taken from inferior conjunctival cul-de-
sac at all study visits.  Updated to indicate that for neonates and infants <2 
months of age, PCR testing for presence of chlamydia and gonorrhea at 
baseline will also be conducted using the baseline visit sample.
Section title and content fore Section 7.2.3.5 was modified as the lab 
assessments for this study are not standard clinical laboratory assessments.
Section 7.2.3.5
Description of the ODS was updated to note that there are 3 components 
to the assessment: pain, itching, and foreign body sensation. It was also 
noted that a separate scale will be administered for children less than 8 
years of age.
Section 7.2.3.7
Section 8.1.5 “Clinical Laboratory and Other Safety Evaluations” was 
removed from the original protocol as these assessments are not a 
component of this study. Laboratory and other relevant assessments may
still be conducted in response to an AE and the PI can make a 
Previous Section 8.1.5


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determination of medical significance based on the results.
Clarified that All efficacy analyses will be based on the mITT population 
with post-baseline LOCF for the subjects with missing clinical resolution 
status at who drop out before Visit 3 (Day 6).  
Section 9.6
It was noted that exploratory efficacy endpoints will be performed on the 
mITT population and will be presented by treatment group.
It was clarified that for both efficacy and safety analyses, baseline is 
defined as the assessments taken at Visit 1 (Day 1).
Section 9.8
Description of the analysis of the primary endpoint was updated as 
follows:
The primary efficacy endpoint of is clinical resolution status (defined as 
absence [ie a score of 0] of bulbar conjunctival injection and watery 
conjunctival discharge) in the study eye at Visit 3 (Day 6) between 
SHP640 and placebo.
All efficacy analyses will be analyzed based performed on the mITT 
population and presented by treatment groups. There is a single primary 
comparison for the single primary endpoint. Therefore, no adjustment of 
multiplicity is needed for the hypothesis testing for the primary objective. 
The primary efficacy endpoint of clinical resolution in the study eye at 
Visit 3 (Day 6) will be compared between the SHP640 and placebo group. 
The comparison will be based on the proportion of subjects with clinical 
resolution in the study eye at Visit 3 (Day 6) using Fisher’s Exact test at 
two sided 0.05 significance level. 
If subjects have missing clinical resolution status at drop out of the study 
before Visit 3 (Day 6), then the last post-baseline observation will be 
carried forward (LOCF) for the determination of clinical resolution of the 
study eye. 
The null hypothesis to be tested is that there is no difference in proportion 
of subjects with clinical resolution in the study eye between SHP640 
Ophthalmic Solution and Placebo with the alternative of the non-zero 
difference in the proportion with clinical resolution between them.
The proportion of subjects with clinical resolution will be compared with 
two-sided Fisher’s Exact test at 5% level of significance.
Sensitivity analyses will be done on the primary efficacy endpoint using 
additional statistical method(s) including other methods of imputation of 
missing data. Sensitivity analyses may be conducted in the ITT in addition 
to the mITT. In addition, descriptive statistics will be generated for the 
primary efficacy endpoint by treatment within the overall pediatric 
population (ie birth to 18 years) and within each pediatric age stratum (< 6 
years and 6 to <18 years) in mITT. A detailed analysis plan for primary 
analysis including additional methods to be usedsensitivity analyses will 
be described in the Statistical Analysis Plan (SAP).
Synopsis
Section 9.6
Section 9.8.2
For key secondary endpoints it was clarified that: 
Synopsis


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All efficacy analyses will be performed on the mITT and presented by 
treatment groups. In order to maintain the study-wide Type I error at 
5.0%, the primary and key secondary hypotheses will be tested 
sequentially using two-sided Fisher’s exact test according to the following 
sequence: 
Sensitivity analyses will also be done on key secondary efficacy endpoints 
using similar methods as described above. In addition, descriptive 
statistics will be generated for the key secondary efficacy endpoint by 
treatment within the overall pediatric population (ie birth to 18 years) and 
within each pediatric age stratum (< 6 years and 6 to <18 years) in mITT. 
Details on the analyses will be described in the Statistical Analysis Plan 
(SAP).
Section 9.8.3
Noted that Binary endpoints will be summarized by number of subjects 
(n), frequencies, proportions and confidence intervals. It was noted that 
Time to event endpoint will be summarized by Kaplan-Meier survival 
estimates. Time to clinical resolution was added.
Section 9.8.4
Section 9.8.5
Noted that safety analyses will be presented by treatment group and 
overall.
Noted that AE assessments will include local tolerability.
Specific components of Slit Lamb Biomicroscopy and Non-dilated/dilated 
fundus examination were added as follows:

Slit Lamp Biomicroscopy
o
Lids 
o
Conjunctiva 
o
Cornea 
o
Anterior Chamber 
o
Iris
o
Lens 

Non-dilated/ Dilated Fundus Examination
o
Vitreous 
o
Optic Nerve 
o
Macula
Synopsis
Section 9.9
It was noted that in case of substantial amendment, approval from the 
Competent Regulatory Authority will be sought before implementation.  
Section 10
Clarified that the investigator, study sponsor and any third party to whom 
aspects of the study management or monitoring have been delegated must 
undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC and its updates, as well as all applicable 
national and local laws and regulations.
Section 10.1.1
Section 10.2.1
Clarified that the documented results of the AdenoPlus test be reviewed, 
not the test itself.
Section 10.2.3.2
Noted that the Operations  Manual will be provided upon request
Appendix 2


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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).

Prot_000.pdf: 
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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Version 1.0/30 June 2016
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA) 


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TABLE OF CONTENTS
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 
randomization strata.


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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 
medical monitor. 


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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 
product is maintained within an established temperature range. The investigator is responsible 


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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).