Clinical trial NCT01694186
Conditions: Non-Infectious Uveitis
Sponsor: EyePoint Pharmaceuticals, Inc.
Start date: 2013-08-02; Completion date: 2018-03-26
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study to evaluate the safety and efficacy of an FAI insert for the management of subjects with non-infectious uveitis affecting the posterior segment of the eye.

Detailed description:
This is a phase 3, multi-national, multi-center, randomized, masked, controlled study to evaluate the safety and efficacy of an injectable fluocinolone acetonide intravitreal (FAI) insert for the management of subjects with non-infectious uveitis affecting the posterior segment of the eye. Patients will be randomized to receive either a sham injection or the FAI insert and will be observed for three years following treatment.

Arms: arm 1: sham injection arm 2: FAI insert (0.18 mg fluocinolone acetonide)
Interventions: intervention 1: FAI insert intervention 2: Sham injection
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
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Fluocinolone Acetonide Intravitreal Insert 
 
pSivida Corp. 
Protocol PSV-FAI-001 [Version 8.1] 
 
Confidential  
 
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FLUOCINOLONE ACETONIDE INTRAVITREAL INSERT 
 
 
PROTOCOL PSV-FAI-001 
 
 
A PHASE III, MULTI-NATIONAL, MULTI-CENTER, RANDOMIZED, 
MASKED, CONTROLLED, SAFETY AND EFFICACY STUDY OF A 
FLUOCINOLONE ACETONIDE INTRAVITREAL (FAI) INSERT IN 
SUBJECTS WITH CHRONIC NON-INFECTIOUS UVEITIS AFFECTING THE 
POSTERIOR SEGMENT OF THE EYE 
 
IND Number 113140 
Eudra CT 2013-001810-14 
CTRI Number CTRI/2014/07/004726 
 
 
Protocol Release Date: October 20, 2015 
 
Version 8.1 
 
pSivida Corp. 
480 Pleasant Street 
Watertown, MA 02472 USA 
 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from pSivida Corp.  Investigators are cautioned 
that the information given in this brochure might be subject to change and revision.  Any 
conclusion regarding efficacy and safety must be considered provisional. 


Fluocinolone Acetonide Intravitreal Insert 
 
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Protocol PSV-FAI-001 [Version 8.1] 
 
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INVESTIGATOR’S AGREEMENT 
 
I have read the attached protocol, concur that it contains all information necessary to conduct the 
study, and agree to follow the study procedures as outlined in this protocol. 
 
I agree to comply with FDA regulations (21 CFR Parts 50, 54, 56 and 312) and ICH guidelines.  
I will not initiate the study until I have obtained written approval by the appropriate Institutional 
Review Board/Ethics Committee and have complied with all financial and administrative 
requirements of the governing body of the clinical institution.  I will obtain written informed 
consent from all study participants prior to performing any screening procedures. 
 
This protocol and related information is subject to the Confidentiality Agreement between 
myself and pSivida Corp. and as such must be held in confidence and not disclosed to any third 
party for a period of seven (7) years from the date of the Confidentiality Agreement, or until said 
information shall become a matter of public knowledge, or until a formal written agreement for 
that purpose has been entered into by the parties. 
 
 
 
_____________________________  
____________ 
 
Principal Investigator Signature  
 
Date 
 
_____________________________ 
Print Name 


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1. 
PERSONNEL CONTACT INFORMATION 
 
Role in Study 
Name 
Address and Telephone Number 
Sponsor 
pSivida Corp. 
480 Pleasant Street 
Watertown, MA 02472 USA 
Phone: (617) 926-5000 
Fax: (617) 926-5050  
Principal Investigator 
Glenn Jaffe, MD 
Duke University Eye Center 
Box 3802, Erwin Road 
Durham, NC 27710 USA 
Medical Monitor 
Svetlana Spassova, MD 
Senior Medical Director 
PPD Bulgaria 
Business Center Megapark, 4th floor  
115 G Tsarigradsko Shosse Blvd. 
Sofia 1784, Bulgaria 
Telephone:  +44 1223 374 240 
Drug Safety Physician 
Svetlana Spassova, MD 
Senior Medical Director 
PPD Bulgaria 
Business Center Megapark, 4th floor  
115 G Tsarigradsko Shosse Blvd. 
Sofia 1784, Bulgaria 
Telephone:  +44 1223 374 240 
24-Hour Emergency Contact 
PPD Support Center 
 
Europe, Asia-Pacific, Africa, 
Middle East sites: 
Medical Support Center 
Telephone:  +44 1223 374 240 
Telefax: 
+44 1223 374 102 
 
North America sites: 
Medical Support Center 
Telephone: 888-483-7729 
Telefax: 
888-529-3580 
Contract Research Organization 
(CRO) 
Suzanne Pio 
Global Project Manager 
3900 Paramount Parkway 
Morrisville, NC 27540 USA 
919- 428-5231 
 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
pSivida Corp. 
Individual Study Table 
Referring to Part 
of the Dossier 
 
Volume: 
 
Page: 
 
(for National Authority 
Use only) 
Name of Investigational Product: 
Fluocinolone Acetonide Intravitreal Insert 
Name of Active Ingredient: 
Fluocinolone Acetonide 
Title of Study:  A Phase III, Multi-National, Multi-Center, Randomized, Masked, Controlled, Safety 
and Efficacy Study of a Fluocinolone Acetonide Intravitreal (FAI) Insert in Subjects with Chronic Non-
Infectious Uveitis Affecting the Posterior Segment of the Eye 
Studied Period (years): 3 years 
Phase of Development: 3 
Objectives:  To evaluate the safety and efficacy of a FAI insert in the management of subjects with 
chronic non-infectious uveitis affecting the posterior segment of the eye.  
Methodology:  A 36 month, multicenter, randomized, controlled, masked safety and efficacy study. 
Number of Subjects (planned):  Approximately 120 subjects (80 FAI insert: 40 sham injection) at 
approximately 40 to 50 sites.  One eye in each subject will be designated as the study eye. 
Diagnosis and Main Criteria for Inclusion:  
Diagnosis: 
Unilateral or bilateral chronic non-infectious uveitis affecting the posterior segment of the eye 
 
Inclusion Criteria: 
• Male or non-pregnant female at least 18 years of age at time of consent 
• One or both eyes having a history of recurrent non-infectious uveitis affecting the posterior 
segment of the eye with or without anterior uveitis > 1 year duration 
• During the 12 months prior to enrollment (Day 1),  
the study eye has either received treatment: 
• 
systemic corticosteroid or other systemic therapies given for at least 3 months, and/or  
• 
at least 2 intra- or peri-ocular administrations of corticosteroid for management of uveitis 
OR the study eye has experienced recurrence: 
• 
at least 2 separate recurrences of uveitis requiring systemic, intra- or peri-ocular injection of 
corticosteroid  
• At the time of enrollment (Day 1), study eye has < 10 anterior chamber cells/HPF and a vitreous 
haze ≤ grade 2. 
• Visual acuity of study eye is at least 15 letters on the ETDRS chart 
• Subject is not planning to undergo elective ocular surgery during the study 
• Subject has ability to understand and sign the Informed Consent Form 
• Subject is willing and able to comply with scheduled visits, treatment plan, laboratory tests and 
other study procedures 
 


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Exclusion Criteria: 
• Allergy to fluocinolone acetonide or any component of the FAI insert 
• History of posterior uveitis only that is not accompanied by vitritis or macular edema 
• History of iritis only and no vitreous cells, anterior chamber cells or vitreous haze 
• Uveitis with infectious etiology  
• Vitreous hemorrhage 
• Intraocular inflammation associated with a condition other than noninfectious uveitis (e.g. 
intraocular lymphoma) 
• Ocular malignancy in either eye, including choroidal melanoma 
• Toxoplasmosis scar in study eye or scar related to previous viral retinitis  
• Previous viral retinitis 
• Current viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis 
(dendritic keratitis), vaccinia, and varicella, mycobacterial infections of the eye or fungal diseases 
of ocular structures 
• Media opacity precluding evaluation of retina and vitreous 
• Peripheral retinal detachment in area of insertion  
• Diagnosis of any form of glaucoma or ocular hypertension in study eye at Screening, unless study 
eye has been previously treated with an incisional surgery procedure that has resulted in stable 
IOP in the normal range (10-21 mmHg) 
• Intraocular pressure (IOP) > 21 mmHg or concurrent therapy at screening with any IOP-lowering 
pharmacologic agent in the study eye  
• Chronic hypotony (< 6 mmHg) 
• Ocular surgery on the study eye within 3 months prior to study Day 1 
• Capsulotomy in study eye within 30 days prior to study Day 1 
• Prior intravitreal treatment of study eye with Retisert within 36 months prior to study Day 1 
• Prior intravitreal treatment of study eye with Ozurdex within 6 months prior to study Day 1 
• Prior intravitreal treatment of study eye with Triesence or Trivaris within 3 months prior to study 
Day 1  
• Peri-ocular or subtenon steroid treatment of study eye within 3 months prior to study Day 1 
• Subjects requiring chronic systemic or inhaled corticosteroid therapy (>15mg prednisone daily) 
or chronic systemic immunosuppressive therapy  
• Excluding certain skin cancers (specifically, basal cell carcinoma and squamous cell carcinoma), 
any malignancy receiving treatment, or in remission less than 5 years prior to study Day 1 
• Subjects who test positive for human immune deficiency virus (HIV) or syphilis during screening 
• Mycobacterial uveitis or chorio-retinal changes of either eye which, in the opinion of the 
Investigator, result from infectious mycobacterial uveitis  
• Systemic infection within 30 days prior to study Day 1 
• Any severe acute or chronic medical or psychiatric condition that could increase the risk 
associated with study participation or could interfere with the interpretation of study results and, 
in the judgment of the investigator, could make the subject inappropriate for entry into this study 
• Any other systemic or ocular condition which, in the judgment of the investigator, could make 
the subject inappropriate for entry into this study 


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• Treatment with an investigational drug or device within 30 days prior to study Day 1 
• Pregnant or nursing females; females of childbearing potential who are unwilling or unable to use 
an acceptable method of contraception as outlined in this protocol from at least 14 days prior to 
study Day 1 until the Month 12 Visit 
• Subjects unlikely to comply with the study protocol or who are likely to be lost to follow-up 
within three years 
Treatment Assignment: 
All study subjects will be randomized (2:1) to receive either a FAI insert (the test article) or a sham 
injection in the designated study eye.  Randomization will be stratified on the basis of whether the 
patient is receiving systemic treatment to control uveitis at the time of study entry.  For patients 
receiving systemic treatment at time of study entry, randomization will be stratified on the basis of the 
type of treatment (steroid or immunosuppressant). 
Control: 
Sham injection 
Duration of Treatment: 
36 months 
Reference Therapy, Dosage and Mode of Administration:  
Reference therapy: Sham injection, followed by standard of care 
Test article therapy: Fluocinolone Acetonide Intravitreal insert (FAI insert).  The FAI insert contains 
0.18 mg FA and delivers FA into the vitreous humor for 36 months.  The FAI insert will be administered 
to the study eye by injection through the pars plana using a pre-loaded applicator with a 25 gauge 
needle. 
Designation/Randomization of Study Eye: 
For subjects with unilateral uveitis, the study eye will be the affected eye; for subjects with bilateral 
uveitis, the study eye will be the more severely affected eye fitting the inclusion/exclusion criteria (i.e. 
the eye having suffered more recurrences in the previous year, or if equal, the eye having received more 
therapy in the previous year, or if equal, the eye having the worse VA or if equal, the eye clinically 
judged to be the more severely affected eye.)  If the eyes are symmetrically affected, the study eye will 
be the right eye. 
Study Procedures: 
Screening (within 30 days prior to injection): 
Eligibility determination, informed consent, demographics, medical and ophthalmic history including a 
detailed history of the management of their uveitis over the previous 12 months, vital signs, clinical labs, 
physical exam, ophthalmic exam (includes BCVA, IOP, dilated ophthalmoscopy and anterior, posterior 
and intermediate slit lamp examination), visual field, subjective ocular tolerability and discomfort 
assessment, concomitant medications and a pregnancy test, as appropriate. 
Treatment Day (Day 1): 
Eligibility confirmation; including meeting the entry criteria for anterior chamber cells, vitreous haze, 
IOP and visual acuity on study Day 1.  Following randomization (via IVRS), subjects will receive the 
FAI insert or sham injection.  Assessments on that day will include vital signs, ophthalmic exam, OCT, 
subjective ocular tolerability and discomfort assessment, pregnancy test, concomitant medications, and 
adverse events (AEs). 
Follow-up Visits: 
Following injection on Study Day 1, subjects will return on Study Days 7, 28 and Months 2, 3, 6, 9, 12, 
18, 24, 30 and 36.  Evaluations on these days include: concomitant medications, vital signs, ophthalmic 


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exam, OCT, subjective ocular tolerability and discomfort assessment, and AEs. 
All subjects enrolled in the study will be followed for 36 months. 
 
Masking:  
To minimize bias, two investigators will participate at each site.  One investigator will administer study 
treatments and perform study Day 1 assessments.  The second investigator will be masked to the 
assigned treatment and will perform all study assessments after study Day 1.  Study personnel will use 
every reasonable effort to maintain the study masking. 
Concomitant Medications: 
Subjects may be treated prior to entry in order to meet study inclusion criteria and obtain a relatively 
quiet eye prior to enrollment.  If a subject is receiving a systemic treatment regimen or topical steroids to 
control uveitis prior to study enrollment, that subject will have such treatment ended within three 
months following study Day 1, in a manner that follows the standard of care for ending the specific 
treatment.  For example, some systemic treatments may be ended immediately, while others require a 
period of gradual dose reduction (tapering). 
If a subject experiences a recurrence of uveitis in either eye that requires treatment during the study, 
local (topical, periocular or intraocular) treatment will be used as the first line of therapy.  Systemic 
immunosuppressants or systemic steroids will be used only if local therapy fails.  Subjects who 
experience a recurrence of uveitis will continue in the study; once the subject’s recurrence is controlled, 
the treatment regimen will be ended in a manner that follows the standard of care for ending the specific 
treatment regimen. 
Criteria for Evaluation: 
Efficacy: 
Primary Efficacy Endpoint: Proportion of subjects who have a recurrence of uveitis in the study eye 
within 6 months after receiving study treatment.  Recurrence is defined as: 
• 
A > 2 step increase in the number of cells in the anterior chamber per high powered field 
(1.6 X using a 1-mm beam), compared to any visit time point prior to Month 6  
OR 
• 
An increase in the vitreous haze of > 2 steps, compared to any visit time point prior to 
Month 6  
OR 
• 
A deterioration in visual acuity of at least 15 letters BCVA, compared to any visit time point 
prior to Month 6 
Any criterion used to define recurrence must be attributable only to noninfectious uveitis.  To prevent 
post-procedural inflammatory reactions from being reported as uveitis recurrences, assessments for 
recurrence of uveitis begin after study Day 7 visit. 
Exploratory Efficacy Endpoints: 
• 
Proportion of subjects who have a recurrence of uveitis in the study eye within 12 months or 
36 months 
• 
Proportion of subjects who have a recurrence of uveitis in the fellow eye (within 6 months, 
12 months and 36 months) 
• 
Mean change from baseline in BCVA letter score in the study eye (at 6 months, 12 months 
and 36 months) 
• 
Number of recurrences of uveitis (within 6 months, 12 months and 36 months) 


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• 
Time to recurrence of uveitis (within 6 months, 12 months and 36 months) 
• 
Number of adjunctive treatments required to treat recurrences of uveitis (within 6 months, 
12 months and 36 months) 
• 
Resolution of macular edema, as measured by OCT imaging (at 6 months, 12 months and 
36 months) 
Safety: 
• 
Systemic adverse events 
• 
Ocular adverse events, including IOP elevation; medications/procedures required to control 
elevated IOP; development or worsening of cataract; cataract-related procedures; clinically 
significant ocular changes; procedure related adverse events 
Statistical Methods: 
Sample Size: 
A two group continuity corrected Chi-square test with a 0.05 two-sided significance level will have 89% 
power to detect the difference between a Sham group recurrence free rate of 0.600 and a FAI treated 
group recurrence free rate of 0.880 (odds ratio of 0.205) when the sample sizes are 40 and 80, 
respectively (a total sample size of 120). 
 
Study Populations: 
The ITT (Intent to Treat) population will include all subjects randomized into the study; analyzed as 
randomized.  The safety population will include all subjects randomized into the study; analyzed as 
treated.  The per protocol (PP) population will be defined separately for the month 6, month 12 and 
month 36 analyses and will exclude all subjects in the ITT population who meet any of the following 
criteria: 
• 
Received systemic treatment for recurrence of uveitis in fellow eye 
• 
Received an imputed endpoint at the 6 month (or 12 month or 36 month) endpoint of the study 
• 
Failed screening, without exemption but received FAI insert 
• 
Had a major protocol deviation 
 
Efficacy Analyses: 
Efficacy analyses will be performed on both the ITT population and the PP population at 6, 12 and 36 
months.  The primary efficacy analysis will be performed on the ITT population at 6 months and will 
be the difference between study groups in the proportion of subjects who have a recurrence of 
uveitis.  The primary efficacy analysis will be conducted after all subjects in the study have completed 6 
months of treatment or have discontinued.  A continuity corrected Chi-square analysis will be used to 
assess the statistical significance of a difference between study groups in the primary efficacy analysis. 
 
Recurrence will be imputed in the following circumstances: 
• 
A subject who has not previously experienced a recurrence and does not complete the required 
eye examinations at Month 6 (or Month 12 or 36 for the Month 12 or 36 analyses, respectively) 
for any reason will be considered as having a recurrence. 
• 
A subject who has not previously experienced a recurrence and takes a prohibited systemic 
concomitant medication or a prohibited local concomitant medication in the study eye at any 
time during the study prior to Month 6 (or Month 12 or 36 for the Month 12 or 36 analyses, 
respectively) will be considered as having a recurrence.   


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Systemic medications or topical steroids administered as part of gradual dose reduction (tapering) (as 
described in Section 9.10.1) will not be considered prohibited medications.  Topical steroids 
administered as part of short term standard treatment following an ocular surgical procedure will also 
not be considered prohibited medications (as described in Section 9.10.2). 
Sensitivity analyses for the primary outcome at 6, 12 and 36 months will be employed.  These analyses 
will include an analysis where a subject imputed as having a recurrence due to missing eye examinations 
at Month 6 (or Month 12 or 36 for the Month 12 or 36 analyses, respectively) will NOT be considered as 
having a recurrence, plus a “tipping point” analysis.  Additionally, for missing data due to other reasons, 
sensitivity analyses will be conducted by using multiple imputation methods. 
Descriptive statistics only will be used in all exploratory efficacy analyses.  Exploratory efficacy 
outcomes will be described by treatment group. 
Safety Analyses: 
Safety analyses will be performed on the safety population at 6, 12 and 36 months.  Descriptive 
statistics will be provided for all treatment emergent adverse events.  Frequency counts and 
percentage of subjects within each treatment group will be provided by MedDRA SOC and 
preferred term by treatment.  Vital signs will be presented using descriptive statistics by treatment 
by visit.  Concomitant medication will be presented by treatment after coding with WHO-Drug 
Dictionary terms.  Laboratories assessments will be presented by descriptive statistics. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
1. 
PERSONNEL CONTACT INFORMATION ..............................................................3 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............10 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................14 
5. 
INTRODUCTION ......................................................................................................15 
5.1. 
Uveitis .........................................................................................................................15 
5.2. 
Current Treatments for Uveitis ...................................................................................15 
5.3. 
Summary of Data for Intravitreal Fluocinolone Acetonide ........................................16 
5.4. 
Study Rationale ...........................................................................................................21 
5.5. 
Description of the FAI insert (Test Article) ...............................................................23 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................25 
6.1. 
Primary Objective .......................................................................................................25 
7. 
INVESTIGATIONAL PLAN .....................................................................................25 
7.1. 
Overall Study Design ..................................................................................................25 
7.2. 
Number of Subjects ....................................................................................................25 
7.3. 
Control ........................................................................................................................25 
7.4. 
Measures Taken to Minimize Bias .............................................................................25 
7.5. 
Number of Study Centers ...........................................................................................25 
7.6. 
Study Duration ............................................................................................................25 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................28 
8.1. 
Subject Inclusion Criteria ...........................................................................................28 
8.2. 
Subject Exclusion Criteria ..........................................................................................28 
9. 
STUDY PROCEDURES ............................................................................................30 
9.1. 
Subject Screening and Informed Consent...................................................................30 
9.2. 
Assignment of Subject Identification Number ...........................................................30 
9.3. 
Randomization ............................................................................................................30 
9.4. 
Screen Failures ............................................................................................................31 


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9.5. 
Study Schedule ...........................................................................................................31 
9.6. 
Screening ....................................................................................................................31 
9.7. 
Procedures on Day of Treatment ................................................................................32 
9.8. 
Criteria for FAI Insert Removal .................................................................................34 
9.9. 
Post-Treatment Visits and Long Term Follow-up ......................................................34 
9.10. 
Concomitant Medications/Procedures ........................................................................35 
9.11. 
Unscheduled Follow-up Visits ...................................................................................36 
9.12. 
Treatment of Recurrences of Uveitis ..........................................................................36 
9.13. 
Description of Procedures ...........................................................................................36 
9.14. 
Laboratory Testing ......................................................................................................37 
9.15. 
Protocol Deviations ....................................................................................................37 
9.16. 
Study Termination or Suspension ...............................................................................37 
9.17. 
Subject Withdrawal Criteria .......................................................................................38 
10. 
INVESTIGATIONAL MATERIALS ........................................................................38 
10.1. 
Test Article .................................................................................................................38 
10.2. 
Sham Injector ..............................................................................................................39 
10.3. 
Supply and Accountability of Materials .....................................................................39 
11. 
ASSESSMENT OF SAFETY .....................................................................................40 
11.1. 
Adverse and Serious Adverse Events .........................................................................40 
11.2. 
Adverse Event Assessment .........................................................................................42 
11.3. 
Recording of Adverse Events .....................................................................................43 
11.4. 
Adverse Event Reporting ............................................................................................44 
11.5. 
Expedited Safety Reporting ........................................................................................45 
12. 
REPORTING OF TECHNICAL COMPLAINTS......................................................47 
13. 
ASSESSMENT OF EFFICACY ................................................................................48 
13.1. 
Primary Efficacy Endpoint .........................................................................................48 
13.2. 
Exploratory Efficacy Endpoints: ................................................................................48 
14. 
DATA ANALYSES ...................................................................................................49 
14.1. 
Sample Size ................................................................................................................49 
14.2. 
Study Populations .......................................................................................................49 
14.3. 
Analyses ......................................................................................................................49 
15. 
ADMINISTRATIVE AND REGULATORY CONSIDERATIONS .........................53 
15.1. 
Quality Control and Quality Assurance ......................................................................53 


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15.2. 
Institutional Review Boards / Independent Ethics Committee ...................................53 
15.3. 
Informed Consent Process ..........................................................................................54 
15.4. 
Source Documentation ................................................................................................54 
15.5. 
Electronic Case Report Forms ....................................................................................55 
15.6. 
Retention of Study Records ........................................................................................55 
15.7. 
Monitoring of the Study..............................................................................................55 
15.8. 
Discontinuation of the Study ......................................................................................55 
15.9. 
Policy for Publications ................................................................................................56 
16. 
ETHICS ......................................................................................................................56 
16.1. 
Ethics Review .............................................................................................................56 
16.2. 
Ethical Conduct of the Study ......................................................................................56 
16.3. 
Written Informed Consent ..........................................................................................56 
17. 
LIST OF REFERENCES ............................................................................................57 
18. 
APPENDIX I: MEASUREMENT OF BCVA BY ETDRS .......................................58 
18.1. 
Refraction Technique ..................................................................................................60 
18.2. 
4-Meter Test and 1-Meter Test ...................................................................................63 
19. 
APPENDIX 2: METHODS OF CLINICAL EVALUATION ...................................65 
19.1. 
Ophthalmoscopy and Grading of Vitreous Haze ........................................................65 
19.2. 
Intraocular Pressure ....................................................................................................67 
19.3. 
Humphrey Visual Field Measurement ........................................................................67 
20. 
APPENDIX 3: SUBJECTIVE OCULAR TOLERABILITY AND 
DISCOMFORT ASSESSMENT ................................................................................67 
 


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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................14 
Table 2: 
Efficacy and Safety of Iluvien and Retisert in DME trials .........................................23 
Table 3: 
IOP-Related Adverse Events Observed in Retisert Clinical Trials ............................23 
Table 4: 
Schedule of Procedures and Assessments ..................................................................27 
 
 
LIST OF FIGURES 
Figure 1: 
FAI Insert ....................................................................................................................24 
Figure 2: 
Study Design ...............................................................................................................26 
Figure 3: 
Vitreous Haze Scoring Convention ............................................................................65 
Figure 4: 
Anterior Chamber Cell Scoring Convention ..............................................................66 
 
  


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AC 
Anterior Chamber 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AMD 
Age Related Macular Degeneration 
BCVA 
Best Corrected Visual Acuity 
CFR 
Code of Federal Regulations  
DME 
Diabetic Macular Edema 
eCRF 
Electronic Case Report Form 
ESR 
Erythrocyte Sedimentation Rate 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ExSR 
Expedited Safety Report 
FA 
Fluocinolone Acetonide 
FAI Insert 
Fluocinolone Acetonide Intravitreal Insert  
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practices 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug application 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
NDA 
New Drug Application 
OCT 
Optical Coherence Tomography 
PI 
Principal Investigator; the investigator who leads the study conduct at an individual study center.   
PP 
Per-Protocol 
PVA 
Polyvinyl Alcohol  
SAE 
Serious Adverse Event 
SAP 
Statistical Analyses Plan 
SOC 
Standard of Care 
SOP 
Standard Operational Procedure 
VA 
Visual Acuity 
WOCBP 
Women of Child Bearing Potential 


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5. 
INTRODUCTION 
pSivida Corp. is developing a drug product candidate to treat chronic non-infectious uveitis 
affecting the posterior segment of the eye.  This includes posterior uveitis, intermediate uveitis 
with or without anterior uveitis, and panuveitis. 
pSivida’s product candidate is an intravitreal insert that contains 0.18 mg of fluocinolone 
acetonide (FA) and releases FA into the vitreous humor for 36 months.  In this protocol, this 
specific drug product candidate is abbreviated as “FAI insert” (for fluocinolone acetonide 
intravitreal insert). 
The clinical trial described in this protocol will be conducted in compliance with the protocol, 
Good Clinical Practices (GCP) as well as all applicable regulatory requirements. 
5.1. 
Uveitis 
Uveitis is defined as inflammation of the uveal tract (iris, ciliary body, choroids) or adjacent 
structures.  The cause of inflammatory reaction of the inner eye can be infectious, traumatic, 
neoplastic or autoimmune.  According to the classification scheme recommended by the 
International Uveitis Study Group, the disease can be classified on the basis of anatomic 
locations: anterior, intermediate, posterior, or panuveitis. 
Uveitis has been estimated to be responsible for approximately 10% of blindness in the United 
States (Suttorp-Schulten 1996).  Generally, posterior uveitis occurs in all age groups and affects 
people of different ethnic origins.  The inflammation that affects the choroid and retina may be a 
primary intra-ocular process or may be an ocular manifestation of systemic disease.  Posterior 
uveitis accounts for most of the loss of vision in eyes with uveitis, due to any one or more of the 
following: cystoid macular edema, choroidal neovascularization, glaucoma, retinal detachment, 
subretinal fibrosis, cataract, or optic disk atrophy. 
5.2. 
Current Treatments for Uveitis 
Uveitis is often a chronic disease requiring long-term medical therapy.  Currently, medical 
management of chronic non-infectious uveitis affecting the posterior segment generally includes 
local administration of corticosteroid (topical, intra- or peri-ocular, intravitreal) and/or systemic 
administration of steroids or immunosuppressants.  Immunosuppressive therapy is used for 
patients with severe uveitis who are unresponsive to corticosteroid therapy or for patients with 
severe corticosteroid-induced complications or who are otherwise intolerant of corticosteroid 
therapy.  The goal of therapy is to suppress the inflammation in the back of the eye. 
There are disadvantages associated with each of these therapies and their route of administration.  
All corticosteroid therapy, including systemic, is associated with ocular side effects, including 
cataract and elevated intraocular pressure (IOP); these side effects are more commonly observed 
with local therapy.  Topical corticosteroid delivery is not effective in the treatment of 
intermediate or posterior uveitis due to its limited intraocular penetration.  Peri-ocular 
corticosteroid injections may be required frequently and have the additional potential risk for 
globe perforation, orbital fibrosis, endophthalmitis and ptosis. 


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Corticosteroids currently approved for the intravitreal treatment of posterior uveitis include 
Retisert®, Ozurdex®, Triesence® and Trivaris®.  Despite the availability of these approved 
products for intravitreal therapy of uveitis of the posterior segment, systemic corticosteroids are 
often required to treat uveitis (MUST group 2011).  However, long term use of systemic 
corticosteroids is associated with significant systemic side effects (Brunton 2006) and may not 
be a practical option for many patients. 
A product that is relatively simple to administer and delivers corticosteroid locally for an 
extended period of time may offer significant benefits over existing local and systemic steroid 
therapies. 
5.3. 
Summary of Data for Intravitreal Fluocinolone Acetonide 
The FAI insert to be used in the present study is virtually identical to Iluvien®, an intravitreal 
fluocinolone acetonide product candidate that has been inserted into the eyes of over 800 
subjects with diabetic macular edema (DME), retinal vein occlusion, wet age-related macular 
degeneration (AMD) or dry AMD. 
Additionally, Retisert, a larger FDA-approved intraocular product that requires surgical 
implantation, also contains the same active ingredient as the FAI insert.  Compared to the FAI 
insert, Retisert delivers approximately 3 times as much FA at rates approximately 3 times faster.  
Retisert has been approved by FDA for the treatment of chronic non-infectious uveitis affecting 
the posterior segment of the eye [Retisert prescribing information (June 2001)]. 
5.3.1. 
Nonclinical Data 
Details of the nonclinical data summarized below can be found in the Investigator’s Brochure 
(IB) that accompanies this protocol. 
5.3.1.1. 
Pharmacology 
The affinity of FA for the glucocorticoid receptor in vitro has been confirmed in a number of 
studies.  In animal pharmacology studies, intravitreal FA significantly decreased the severity of 
proliferative vitreoretinopathy in a rabbit model, reduced ocular inflammation in a rabbit uveitis 
model, and showed neuroprotective effects in rodent models of retinal degeneration. 
5.3.1.2. 
Pharmacokinetics 
Nonclinical pharmacokinetic studies in rabbits demonstrated that there is no quantifiable 
systemic exposure of fluocinolone acetonide following intravitreal injection of FA.  FA 
elimination from ocular tissues was very slow and was not apparently tissue or dose dependent.  
The estimated half-life of FA was considered the result of the controlled release of FA from the 
delivery system.  FA exposure was generally highest in the choroid and pigmented epithelium 
followed by the lens or retina, the iris/ciliary body, the vitreous humor or cornea.  The ocular 
exposure of FA in the aqueous humor was minimal at all dose levels.  The observed exposure 
profiles are consistent with the mode of administration of FA. 


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5.3.1.3. 
Toxicology 
FA-related findings in the rabbit toxicity studies were limited to the eye.  Cataracts and/or lens 
fiber degeneration were observed by ophthalmological examination and/or histopathological 
evaluation in two studies (9 and 24 month duration) and may be related to pharmacologic effects 
of FA.  The 24-month toxicity study observed dose-dependent increase in the frequency and 
severity of cataracts at nominal daily doses of 0.5 and 1.0 μg FA/day; however, there were no 
apparent ocular effects at a nominal daily dose of 0.2 μg FA/day.  Other ocular findings (e.g., 
focal retinal scarring) were considered likely related to experimental procedures, rather than FA 
itself.  
No systemic toxicity was observed in either study.  The absence of characteristic systemic effects 
of glucocorticoids such as body weight gain, Cushingoid syndrome, reductions in lymphocytes 
and lymphoid organ weights, and hepatic glycogen deposition and fatty liver changes (Brunton 
2006) was most likely due to the minimal systemic exposure resulting from the intravitreal route 
of administration.  FA was not genotoxic in a core battery of in vitro and in vivo tests.  
Carcinogenicity and developmental/reproductive studies have not been conducted because FA 
systemic exposure is very low following intravitreal administration.  FA has been previously 
shown to be teratogenic and an abortifacient in rats and rabbits (Kihlstrom 1987; Casilli 1977).  
However, the doses of FA that produced these developmental and reproductive effects are 
several thousand-fold higher than the amount of FA per day released by the FAI insert. 
5.3.2. 
Clinical Data 
Details of the clinical data summarized below can be found in the Investigator’s Brochure (IB) 
that accompanies this protocol.  There are two products related to the FAI insert (Retisert® and 
Iluvien®) for which there is considerable previous human experience that is relevant to the 
clinical evaluation of the FAI insert. 
5.3.2.1. 
Previous Human Experience with Retisert 
Retisert is a sustained release intravitreal product indicated for the treatment of chronic non-
infectious uveitis affecting the posterior segment of the eye [Retisert® Prescribing Information 
(June 2011)].  Retisert contains 0.59 mg FA and is surgically inserted into the affected eye 
through a pars plana incision.  Retisert is designed to release FA at a nominal initial rate of 0.6 
μg FA/day decreasing over the first month to a steady state between 0.3-0.4 μg FA/day over 
approximately 30 months.  Because Retisert and the FAI insert both utilize FA as the active 
ingredient, previous human experience with Retisert identifies potential FA-related safety issues 
that are relevant to the clinical studies proposed for the FAI insert. 
5.3.2.1.1. Chronic Non-infectious Uveitis Affecting the Posterior Segment of the Eye 
FDA approval of Retisert was based on two randomized, double-masked multicenter controlled 
clinical trials that enrolled 224 patients with chronic non-infectious uveitis affecting the posterior 
segment of one or both eyes. 
Efficacy 
The primary efficacy endpoint in both trials was the rate of recurrence of uveitis affecting the 
posterior segment of the study eye in the 34 week pre-implantation period compared to the 


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rate of recurrence at the 34 week post-implantation period.  Both studies demonstrated that 
recurrences occurred significantly less frequently in the Retisert treatment group compared to 
historic control (Study 1: 1.8% vs. 53.7%; Study 2: 12.9% vs. 39.7%, respectively). 
Safety 
Nearly all phakic eyes treated with Retisert developed cataracts and required cataract surgery 
over a three year period.  Additionally, over a three year period, approximately 77% of 
patients receiving Retisert required medication to control elevated IOP and 37% required 
filtering operations to control elevated IOP.  Note: these trials included patients who at 
baseline had an IOP as high as 25 mmHg while receiving as many as two medications to 
control IOP. 
The above risks are consistent with risks generally associated with intraocular corticosteroid 
administration, which have also been previously shown to be associated with posterior 
subcapsular cataract formation and elevated IOP and/or glaucoma. 
Cases of late onset endophthalmitis were also observed in these trials, often related to the 
integrity of the wound site.  Other surgical complications include choroidal detachment, 
hypotony, increased intraocular IOP, retinal detachment, vitreous hemorrhage, wound 
dehiscence, and exacerbation of ocular inflammation. 
5.3.2.1.2. Diabetic Macular Edema (DME) 
Retisert has been evaluated in a clinical study of 198 patients with DME (Pearson 2011). 
Efficacy 
Two years after enrollment, 31.8% of Retisert-treated patients experienced an improvement 
in BCVA of at least 15 letters, versus 9.3% of SOC-treated patients.  This difference was 
statistically significant (p = 0.0016).  Three years after enrollment 31.1 % of Retisert-treated 
patients experienced an improvement in BCVA of at least 15 letters, versus 20.0% of SOC-
treated patients.  This difference was not statistically significant. 
Safety 
Nearly all phakic eyes treated with Retisert developed cataracts and required cataract surgery 
over a four year period.  Additionally, 61.4% of patients receiving Retisert experienced IOP 
≥ 30 mmHg and 33.8% required surgical intervention to control IOP.  Surgery-related 
adverse events reported in this trial were similar to those reported in the uveitis studies 
described in Section 5.3.2.1.1.  Note: this trial included patients who at baseline had an IOP < 
21mmHg while receiving no more than one IOP lowering medication. 
The types and incidences of adverse events associated with Retisert in this DME clinical trial 
were highly similar to those reported for Retisert in the uveitis clinical trials described in 
Section 5.3.2.1.1. 
5.3.2.2. 
Previous Human Experience with Iluvien 
Iluvien is an intravitreal product candidate that is designed to provide long term delivery of FA 
and is administered by injection.  Iluvien was invented by pSivida and licensed to Alimera 
Sciences, Inc. for certain ophthalmic indications, excluding uveitis.  Two Iluvien product 


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candidates were evaluated in clinical trials under IND 072056; both contained 0.18 mg FA.  A 
“high dose” Iluvien insert was designed to provide a nominal initial release rate of 0.5 μg FA/day 
slowing to 0.2 μg FA/day.  A “low dose” Iluvien insert was designed to provide a constant 
nominal release rate of 0.2 μg FA/day for 36 months.  Both inserts were administered by 
intravitreal injection.  Due to similar efficacy and a better safety profile the low dose Iluvien 
insert has been selected for further development by Alimera Sciences. 
The “low dose” Iluvien insert and the FAI insert are virtually the same: 
• The composition of the FAI insert is the same as the composition of the Iluvien insert, 
with respect to active ingredient (FA), excipients (PVA and WFI) and insert 
components (polyimide tubing, silicone adhesive and PVA membrane). 
• The FA release rates of the FAI insert and the “low dose” Iluvien insert are the same; 
both drug products are designed to release FA for 36 months. 
Consequently, previous human experience with Iluvien is highly relevant to the clinical studies 
that evaluate the FAI insert. 
5.3.2.2.1. Pharmacokinetics 
The pharmacokinetics of FA release from high dose or low dose Iluvien inserts in human 
subjects with DME was assessed using plasma and aqueous humor sampling (Campochiaro 
2012). This three year study demonstrated that Iluvien inserts release FA continuously within the 
eye for 36 months, and that FA is not measurable in the plasma at any time through 36 months. 
FA levels in the aqueous humor of subjects receiving a low dose Iluvien insert (the same drug 
product as the FAI insert) were initially 2 ng/mL (month 1), gradually decreasing to 0.5 ng/mL 
(month 36). 
Systemic FA levels were below the level of detection at all time points. This observation is 
consistent with the low systemic bioavailability of FA associated with an intraocular route of 
administration and the low intraocular daily dose released by the Iluvien inserts. 
These clinical findings are generally consistent with the results of a rabbit pharmacokinetics 
study (see Section 5.3.1.2 above).  One difference observed between rabbit and human data 
concerns the concentrations of FA detected in the aqueous humor.  In rabbits, FA was typically 
not detected in the aqueous humor; in humans, FA was detected in the aqueous humor at every 
time point through Month 36.  This difference may be due to species differences in ocular 
clearance. 
5.3.2.2.2. Diabetic Macular Edema (DME) 
Two large studies in DME patients (FAME A and B) were performed as randomized, double-
masked, sham injection-controlled, parallel-group, multi-center studies of 36-month duration.  
The studies enrolled patients with DME who had received prior laser photocoagulation and who, 
at baseline, had a retinal thickness ≥ 250 microns. 
The studies both evaluated the “high dose” and “low dose” Iluvien inserts, which were 
administered by intravitreal injection. 


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The entry criteria for the FAME studies were similar to those used in the Retisert DME study 
(Section 5.3.2.1.2), with one notable difference.  In the Retisert DME study, a patient could be 
enrolled if baseline IOP was < 21mmHg while receiving no more than one IOP lowering 
medication.  In the Iluvien DME studies, a patient could be enrolled if baseline IOP was below 
21mm Hg while receiving no IOP-lowering medication.  (Note: Protocol PSV-FAI-001uses this 
same inclusion criterion.) 
Efficacy 
The studies’ primary efficacy endpoint was the proportion of subjects with ≥ 15-letter 
improvement in BCVA at Month 24; the primary efficacy endpoint was also assessed at 
Month 36.  Statistically significant differences (vs. sham) were demonstrated in both 
treatment groups in both studies at 24 months.  The efficacy of the 0.2 μg FA/day dose was 
similar to that of the 0.5 μg FA/day dose. 
Safety 
Systemic Adverse Events 
Since FA released from Iluvien is not measurable in the plasma of humans or rabbits at 
any time following administration, systemic effects related to study drug were not 
expected.  This expectation was consistent with the adverse events collected in the FAME 
studies: of the 1524 treatment emergent adverse events (TEAEs) reported overall in these 
two studies that were considered by the investigator to be drug-related, only 3 events 
were systemic in nature (3 cases of headache). 
A higher incidence of anemia (irrespective of relationship to drug) was observed in 
subjects who received Iluvien compared to sham (3%, sham; 7%, 0.2 μg FA /day; 9%, 
0.5 μg FA /day).  The cause of this increase is not known and was not considered by the 
Data Monitoring Safety Board to be related to FA.  It has been hypothesized that the 
increase may be due to the use of oral carbonic anhydrase inhibitors (CAIs) (which 
occurred more frequently in the active treatment groups).  This class of IOP-lowering 
drugs is known to exacerbate renal dysfunction and possibly compromise erythropoietin 
production.  A post-hoc analysis was performed in which all subjects were categorized 
with or without anemia and with or without a systemic CAI (administered during or 
within 90 days of anemia).  Based on a Pearson chi-square test, there was a relationship 
between the use of a CAI and anemia in the 0.2 μg FA /day group (p-value <0.0001, and 
in the 0.5 μg FA /day group (p=0.0073). 
Deaths and Serious Adverse Events 
A total of 56 (6%) deaths were reported in the FAME studies.  None of the deaths were 
attributed to study drug or unexpected in the patient population. 
A total of 401 (42%) subjects had at least 1 drug-related serious adverse event (SAE), all 
of which were ocular in nature.  The overall incidence of drug-related SAEs was several-
fold higher in the Iluvien insert groups relative to sham. 
Ocular Adverse Events 


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In the FAME Studies, the most common drug-related TEAEs were cataract operation 
(39% of subjects), cataract (36%), increased intraocular pressure (25%), and 
myodesopsia (8%). 
 
Cataract-Related Events in Phakic Subjects 
The FAME studies enrolled 621 subjects with phakic study eyes at baseline; the 
remaining 335 study eyes were pseudophakic at baseline.  The incidence of cataract in 
the study eye was higher in the active treatment groups [80% (low dose), 88% (high 
dose)] than in the sham group (46%).  The most common types of cataracts in the study 
eye were cataract (NOS) and posterior subcapsular cataract, both of which were reported 
more frequently in the active treatment groups than in the sham group.  The percentage of 
phakic subjects who had a cataract operation in the study eye was also higher in the 
active treatment groups [75% (low dose), 85% (high dose)] than in the sham group 
(23%). 
IOP-Related Events and Procedures 
In the study eye, elevated intraocular pressure was reported as a TEAE more frequently 
in the active treatment groups than in the sham group, for the following parameters: 
• 
IOP increase from baseline ≥ 12 mmHg  
• 
IOP value >25 mmHg  
• 
IOP value >30 mmHg 
• 
Surgical intervention to control elevated IOP 
The most common IOP-related procedure in the study eye was trabeculectomy, which 
occurred in 3% of subjects overall.  Other procedures were performed in less than 2% of 
all subjects and included vitrectomy for elevated IOP or device removal, or 
trabeculoplasty in the study eye. 
5.3.2.2.3. Other Patient Populations 
Iluvien is also being evaluated in subjects with age-related macular degeneration, geographic 
atrophy or retinal vein occlusion.  
The interim safety data from these studies are consistent with the safety profile observed for 
Iluvien in DME subjects and do not provide any new safety signal. 
5.4. 
Study Rationale  
pSivida Corp. is developing the FAI insert to provide local steroid therapy with an improved 
benefit/risk profile for patients with chronic non-infectious uveitis affecting the posterior 
segment of the eye.  Specifically, the FAI insert has been designed to: 
Eliminate the need for surgical implantation:  
The FAI insert to be used in the present study is inserted into the eye by injection, using a 
pre-loaded applicator with a 25 g needle.  In contrast, Retisert® devices are surgically 
placed via a 3-4 mm incision. 


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Eliminate the side effects associated with the use of systemic corticosteroids or 
immunomodulating drugs: 
 
Systemic corticosteroids and non-steroidal immunosuppressive agents are currently used 
for treating posterior uveitis.  These therapies often fail because sufficient drug does not 
reach the uveal tissues due to the presence of a “blood-eye” barrier.  Systemic toxicities 
are dose limiting for those medications.  The FAI insert can be injected into the vitreous 
cavity of the eye, where it slowly releases FA over a period of 36 months.  Intravitreal 
delivery of FA minimizes systemic exposure and thereby reduces systemic side effects. 
 
Yield efficacy comparable to Retisert (recurrence of uveitis): 
Although the FA dose delivered by the FAI insert (0.2 μg/day) is lower than the FA dose 
delivered by Retisert (0.5-0.6 μg/day), it is anticipated that the FAI insert will prevent the 
recurrence of uveitis as effectively as Retisert.  This expectation is based upon 
nonclinical and clinical observations: 
 
Nonclinical studies of FA intravitreal administration have demonstrated that FA levels in 
the vitreous humor are 10- to 80-fold higher than FA levels in the aqueous humor, and 
that an FA dose as low as 0.1 μg FA /day controlled inflammation in the posterior 
segment.  In clinical studies, FA concentrations were consistently detected in the aqueous 
humor at levels of 0.5 – 1.0 ng/ml in patients who had received an Iluvien insert 
delivering 0.2 μg/day.  If one applies the nonclinical study findings to these data, then FA 
concentrations in the vitreous humor of these patients should have ranged from 5-80 
ng/ml.  These concentrations are predicted to be sufficiently high to achieve 
pharmacologic activity in the posterior tissues of the eye, given the potency of FA for 
glucocorticoid receptor transactivation in vitro [IC50 ≈ 1 nM (0.45 ng/ml); Nehmé 
2009)]. 
Clinical study results are consistent with this prediction: low dose Iluvien (0.2 μg 
FA/day) and Retisert demonstrated comparable efficacy in DME patients (Table 2). 
 
Yield an improved safety profile compared to Retisert, with respect to elevated IOP 
The use of the FAI insert in uveitis patients is anticipated to result in fewer adverse 
events associated with elevated IOP than have been previously observed with Retisert.  
This expectation is based on a comparison of the safety observed in DME patients of low 
dose Iluvien versus Retisert (Table 2). 


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Table 2: 
Efficacy and Safety of Iluvien and Retisert in DME trials 
Treatment 
[data source] 
Outcome 
Efficacy 
Safety 
BCVA > 15 letters 
IOP > 30 mmHg 
IOP lowering 
surgical 
interventions 
Retisert 
[Pearson 2011] 
31% 
(vs. 9% SOC) 
@ 24 months 
61.4% 
(vs. 5.8% SOC) 
@ 48 months 
33.8% 
(vs.  0% SOC) 
@ 48 months 
“Low dose” Iluvien 
(0.2 μg FA/day)2 
[Alimera Biosciences 
2011] 
28.7% 
(vs. 16.2% sham) 
@ 24 months 
18.4% 
(vs. 4.3% sham) 
@ 36 months 
4.8% 
(vs. 0.5% sham) 
@ 36 months 
 
pSivida expects that the IOP-related safety profile of the FAI insert in uveitis patients 
will be comparable to that of low dose Iluvien in DME patients.  
 
This expectation is predicated on observations from previous clinical trials with 
Retisert: the IOP-related safety profile of Retisert is similar in both DME and uveitis 
patients (Table 3). 
Table 3: 
IOP-Related Adverse Events Observed in Retisert Clinical Trials 
Study 
Safety Outcome 
Elevated IOP 
(AE description) 
IOP lowering 
surgical 
interventions 
Diabetic macular edema 
[Pearson 2011] 
61.4% 
(≥30mmHg) 
@ 48 months 
33.8% 
 
@ 48 months 
Chronic non-infectious 
uveitis affecting the 
posterior segment 
[Retisert Prescribing 
Information (June 2011)] 
77% 
(require medication 
to lower IOP) 
@ 36 months 
37% 
 
 
@ 36 months 
 
5.5. 
Description of the FAI insert (Test Article)  
5.5.1. 
Drug Name 
Fluocinolone acetonide is the active ingredient in the FAI insert. 
Fluocinolone acetonide is a member of a class of fluorinated synthetic corticosteroids that 
includes dexamethasone, triamcinolone acetonide and fluocinolone acetonide. 


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5.5.2. 
Drug Formulation  
FA is combined with one excipient, polyvinyl alcohol (PVA), to form a FA-PVA core (3.5 mm 
length x 0.34 mm diameter) that is contained within a polyimide tube.  The polyimide tube has a 
permeable PVA membrane at one end and an impermeable silicone adhesive plug on the other 
end.  Figure 1 shows the FAI insert adjacent to a grain of rice. 
Figure 1: 
FAI Insert 
 
5.5.3. 
Route of Administration 
The FAI insert is administered as an intravitreal injection.  The FAI insert is provided in a sterile 
preloaded applicator with a 25 g needle and is administered via injection through the pars plana. 
5.5.4. 
Dose and Duration  
The FAI insert contains 0.18 mg FA and delivers FA into the vitreous humor for 36 months, as 
demonstrated in a clinical pharmacokinetics study of Iluvien (Campochiaro 2012).  In vitro data 
demonstrate that initial FA release occurs at a rate of approximately 0.2 μg FA/day, gradually 
decreasing over three years to a rate of approximately 0.1 μg FA/day. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objectives of this study are to evaluate the safety and efficacy of a FAI insert in the 
management of subjects with chronic non-infectious uveitis affecting the posterior segment of 
the eye. 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This trial is a 36 month, Phase 3, multi-national, multi-center, randomized, masked, controlled, 
safety and efficacy study of FAI inserts in subjects with chronic non-infectious uveitis affecting 
the posterior segment of the eye. 
As depicted in Figure 2, subjects will receive either a FAI insert or sham injection on Day 1 of 
the study; subjects will be assessed according to the schedule presented in Table 4. 
7.2. 
Number of Subjects 
A total enrollment of approximately 120 subjects is planned for this study. 
7.3. 
Control 
Sham injection 
7.4. 
Measures Taken to Minimize Bias 
To minimize bias, two investigators will be used at each study site.  One investigator will serve 
as the unmasked treating investigator (Investigator 1) and the other investigator will serve as the 
masked assessing investigator (Investigator 2).   On study Day 1, Investigator 1 will inject the 
FAI insert or perform a sham injection, and will perform all study Day 1 assessments.  All other 
study assessments will be performed by Investigator 2.  Only Investigator 1 will know the 
assigned treatment.  Study personnel will use every reasonable effort to maintain the study mask. 
7.5. 
Number of Study Centers 
This study will be conducted at approximately 40 to 50 study sites. 
7.6. 
Study Duration 
All subjects will be followed for 36 months after treatment. 


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Figure 2: 
Study Design 
 
ELIGIBILITY 
SCREENING
INFORMED 
CONSENT
Eligibility Confirmation,
Randomization, 
Treatment with: 
FAI Insert OR Sham Injection
Month
12
Month
36
ONE YEAR 
EFFICACY AND 
SAFETY ANALYSIS
THREE YEAR 
EFFICACY AND 
SAFETY ANALYSIS
Eligibility
Screen 
Failure
Eligibility
Screen 
Success
Day 
1
Month
6
PRIMARY 
EFFICACY AND 
SAFETY ANALYSIS
 


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Table 4: 
Schedule of Procedures and Assessments 
Assessments 
Screening 
Day  
1 
Day  
7 
Day  
28 
Months 
2, 3 
Months 
6, 9, 12, 18, 
24, 30, 36 
Timing/Interval 
-30 to 0 
1 
±2D 
±3D 
±7D 
±28D 
Medical/Ophthalmic History 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Pregnancy Testa 
X 
X 
 
 
 
Xa 
Vital Signsb 
X 
X 
X 
X 
X 
X 
Clinical Labsc 
X 
 
 
 
 
 
Ophthalmic Examinationd 
X 
X 
X 
X 
X 
X 
Visual Fielde 
X 
 
 
 
 
Xe 
OCT 
 
X 
 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
 
Subjective Ocular Tolerability & Discomfort 
Assessment 
X 
X 
X 
X 
X 
X 
FAI Insert Placement or Sham Injection 
 
X 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
a Females of child-bearing potential only: urine test conducted only at Screening, Day 1, Month 12, Month 24 and Month 36. 
b Includes systolic/diastolic blood pressure and pulse rate after subject is in the sitting position for at least 5 minutes.  Height and weight at Screening only. 
c Hematology; ESR; serum chemistry; urinalysis; HIV and syphilis serology testing; TB testing. 
d Ophthalmic examination includes BCVA, IOP [recorded as the mean of three measurements], dilated indirect ophthalmoscopy, and anterior, posterior and 
intermediate slit lamp examinations 
e Conducted only at Months 12, 24 and 36. 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
• Male or non-pregnant female at least 18 years of age at time of consent 
• One or both eyes having a history of recurrent non-infectious uveitis affecting the 
posterior segment of the eye with or without anterior uveitis > 1 year duration.  
• During the 12 months prior to enrollment (Day 1),  
the study eye has either received treatment: 
o systemic corticosteroid or other systemic therapies given for at least 3 months, 
and/or  
o at least 2 intra- or peri-ocular injections of corticosteroid for management of 
uveitis  
OR the study eye has experienced recurrence: 
o at least 2 separate recurrences of uveitis requiring systemic, intra- or peri-
ocular injection of corticosteroid 
• At the time of enrollment (Day 1), study eye has < 10 anterior chamber cells/HPF and 
a vitreous haze ≤ grade 2. 
• Visual acuity of study eye is at least 15 letters on the ETDRS chart 
• Subject is not planning to undergo elective ocular surgery during the study 
• Subject has ability to understand and sign the Informed Consent Form 
• Subject is willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures 
8.2. 
Subject Exclusion Criteria 
• Allergy to fluocinolone acetonide or any component of the FAI insert 
• History of posterior uveitis only that is not accompanied by vitritis or macular edema 
• History of iritis only and no vitreous cells, anterior chamber cells or vitreous haze 
• Uveitis with infectious etiology 
• Vitreous hemorrhage 
• Intraocular inflammation associated with a condition other than noninfectious uveitis 
(e.g. intraocular lymphoma) 
• Ocular malignancy in either eye, including choroidal melanoma 
• Toxoplasmosis scar in study eye; or scar related to previous viral retinitis 
• Previous viral retinitis 


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• Current viral diseases of the cornea and conjunctiva including epithelial herpes 
simplex keratitis (dendritic keratitis), vaccinia, and varicella, mycobacterial infections 
of the eye or fungal diseases of ocular structure 
• Media opacity precluding evaluation of retina and vitreous 
• Peripheral retinal detachment in area of insertion 
• Diagnosis of any form of glaucoma or ocular hypertension in study eye at Screening, 
unless study eye has been previously treated with an incisional surgery procedure that 
has resulted in stable IOP in the normal range (10-21 mmHg)  
• Intraocular pressure (IOP) > 21 mmHg or concurrent therapy at screening with any 
IOP-lowering pharmacologic agent in the study eye 
• Chronic hypotony (< 6 mmHg) 
• Ocular surgery on the study eye within 3 months prior to study Day 1 
• Capsulotomy in study eye within 30 days prior to study Day 1 
• Prior intravitreal treatment of study eye with Retisert within 36 months prior to study 
Day 1 
• Prior intravitreal treatment of study eye with Ozurdex within 6 months prior to study 
Day 1 
• Prior intravitreal treatment of study eye with Triesence or Trivaris within 3 months 
prior to study Day 1  
• Prior peri-ocular or subtenon steroid treatment of study eye within 3 months prior to 
study Day 1 
• Subjects requiring chronic systemic or inhaled corticosteroid therapy (>15mg 
prednisone daily) or chronic systemic immunosuppressive therapy 
• Excluding certain skin cancers (specifically, basal cell carcinoma and squamous cell 
carcinoma), any malignancy receiving treatment, or in remission less than 5 years 
prior to study Day 1 
• Subjects who test positive for human immune deficiency virus (HIV)or syphilis 
during screening 
• Mycobacterial uveitis or chorio-retinal changes of either eye which, in the opinion of 
the Investigator, result from infectious mycobacterial uveitis 
• Systemic infection within 30 days prior to study Day 1 
• Any severe acute or chronic medical or psychiatric condition that could increase the 
risk associated with study participation or could interfere with the interpretation of 
study results and, in the judgment of the investigator, could make the subject 
inappropriate for entry into this study 
• Any other systemic or ocular condition which, in the judgment of the investigator, 
could make the subject inappropriate for entry into this study 


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• Treatment with an investigational drug or device within 30 days prior to study Day 1 
• Pregnant or nursing females; females of childbearing potential who are unwilling or 
unable to use an acceptable method of contraception as outlined in this protocol from 
at least 14 days prior to study Day 1 until the Month 12 Visit 
• Subjects unlikely to comply with the study protocol or who are likely to be lost to 
follow-up within three years 
9. 
STUDY PROCEDURES 
9.1. 
Subject Screening and Informed Consent 
The investigator will obtain written informed consent from each subject as a condition of 
enrollment in the study.  Informed consent will be obtained after providing the prospective study 
participant with an adequate explanation of the protocol procedures and prior to the subject’s 
participation in the study (including screening procedures). 
The content of the informed consent form (ICF) will conform to FDA regulations as defined in 
21 CFR Part 50, other necessary Regulations, and must have current Institutional Review Board 
(IRB)/ Ethics Committee (EC) approval. 
The subject will sign the ICF before any study procedures are initiated.  The subject or guardian 
will sign and date one or two copies of the ICF in the presence of the investigator or designee, in 
accordance with applicable local requirements.  A signed original copy will be retained with the 
subject records, and either a copy of the signed original or another signed original of the ICF will 
be given to the subject, in accordance with applicable local requirements. .  
9.2. 
Assignment of Subject Identification Number 
Once a subject has provided written informed consent, and it has been determined that the 
subject will undergo screening, a Subject Identification (PtID) Number will be assigned by the 
study site.  The first 2 digits of the PtID number will be the assigned site number as followed by 
a 3-digit number in sequential order (i.e., 01-001, 01-002, etc.). 
The PtID number and subject initials (where permitted by local authorities) are to be recorded on 
all study documents and will link the documents to the subject’s medical record.  To maintain 
confidentiality, the subject’s name should not be recorded on any study document other than the 
ICF. 
Only those patients who have been randomized will have Exclusion/Inclusion data recorded on 
the electronic case report forms (eCRF).  
9.3. 
Randomization 
Following confirmation of eligibility at Day 1, subjects will be randomly assigned in a 2:1 ratio 
to either the FAI insert or sham injection through a central Interactive Voice Response System 
(IVRS).  Randomization will be stratified on the basis of whether the patient is receiving 
systemic treatment to control uveitis at the time of study entry. 


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The randomization schedule will be prepared using a blocked randomization and will be 
generated by an independent statistician. 
The treatment assignment will be revealed to the assessing investigator only in emergency 
situations when medical/supportive care cannot be provided without determining if the subject 
received the FAI insert. 
9.3.1. 
Unmasking 
Unmasking a subject’s treatment to the assessing investigator should only be done in emergency 
situations for reasons of subject safety. 
At the initiation of the study, the clinical sites will receive instructions for unmasking a subject. 
In the event that an emergency unmasking is required, the assessing investigator/medically 
qualified designee has the authority to unmask a subject’s treatment using IVRS, or its back-up 
system if IVRS is not functioning.  , If possible, the assessing investigator/medically qualified 
designee should contact the PPD Medical Monitor or designee before breaking the mask. 
When the masked treatment code is broken, the date and time of unmasking, name of person 
doing the unmasking, and the reason for unmasking must be fully documented in the source 
documentation. 
9.4. 
Screen Failures 
Study centers will document all screen failures on the Subject Screening/Enrollment Log with 
the reason for the failure to be enrolled.  Subjects who fail to meet inclusion/exclusion criteria 
during the screening period or on study Day 1 may be rescreened. 
9.5. 
Study Schedule 
See Table 4 for the schedule of visits and assessments.  The screening visit and Day 1 
(administration of study treatment) are to be within a 30-day period.  The windows for the 
follow-up visits are Day 7: +/- 2 days; Day 28: +/- 3 days; Months 2, 3: +/- 7 days; Months 6, 9, 
12, 18, 24, 30 & 36: +/- 28 days.  
9.6. 
Screening 
All study data will be collected for the study and fellow eye. 
After obtaining informed consent, the following assessments will be performed: 
• Demographic information, medical history and ophthalmic history including a 
detailed history of the subject’s posterior uveitis and its management over the 
previous 12 months 
• Physical exam including height, weight and vital signs (includes systolic/diastolic 
blood pressure and pulse rate after subject is in the sitting position for at least 5 
minutes) 
• Obtain blood samples for routine clinical laboratory tests (hematology, ESR, serum 
chemistry) 


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• HIV and syphilis serology testing  
• TB testing 
• Ophthalmic exam (including BCVA, IOP [recorded as the mean of three 
measurements], dilated indirect ophthalmoscopy and anterior, posterior and 
intermediate slit lamp examinations) 
• Visual field 
• Collect urine for Urinalysis and for Urine pregnancy test (females of childbearing 
potential) 
• Subjective Ocular Tolerability and Discomfort Assessment 
• Concomitant medications 
• Verification that the subject satisfies all inclusion and exclusion criteria.  Do not 
continue screening any subject who does not meet the screening eligibility 
requirements. 
9.7. 
Procedures on Day of Treatment  
9.7.1. 
Designation of Study Eye and Randomization 
For subjects with unilateral uveitis, the study eye will be the affected eye.  For subjects with 
bilateral uveitis, the study eye will be the worse eye meeting the inclusion/exclusion criteria.  For 
subjects with symmetrical uveitis the study eye will be the right eye.  The non-study eye may 
receive any local ocular treatment at the discretion of the investigator. 
If the subject meets the inclusion and exclusion criteria at Screening and Day 1, the 
randomization to the FAI insert or sham injection will be performed via the IVRS.  
Randomization will be stratified on the basis of whether the patient is receiving systemic 
treatment to control uveitis at the time of study entry.  For patients receiving systemic treatment 
at time of study entry, randomization will be stratified on the basis of the type of treatment 
(steroid or immunosuppressant). 
To preserve study masking as much as possible within the imposed ethical constraints, the study 
personnel who administer the assigned treatment will refrain from performing any subject 
assessments after study Day 1.  Treatment assignments will be masked to the subjects and to 
those involved in administering routine follow-up care to the subjects.  Follow-up assessments 
will only be performed by study personnel at the site who are masked to the assigned treatment. 
9.7.2. 
Data Collection Prior to Injection of FAI Insert or Sham Injection 
• Vital signs (blood pressure and pulse rate after subject is in the sitting position for at 
least 5 minutes) 
• Ophthalmic exam (including BCVA, IOP [recorded as the mean of three 
measurements], dilated indirect ophthalmoscopy and slit lamp examinations) 
• Determination of < 10 anterior chamber cells/HPF and a vitreous haze ≤ grade 2 for 
study eye 


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• OCT 
• Urine Pregnancy test 
• Concomitant medications 
• Subjective tolerability and discomfort assessment  
• Verification that the subject satisfies all other inclusion and exclusion criteria 
9.7.3. 
FAI Insert Injection Procedure 
1. Administer a topical antibiotic at the rate of one drop every 5 minutes for a total of 3 
drops prior to the injection of the FAI insert. 
2. Just prior to the insert injection, administer additional topical anesthesia over the 
injection site as one- two drops followed by either a cotton-tipped applicator soaked in 
anesthetic or as subconjunctival administration of lidocaine. 
3. Administer 2-3 drops of 5% Betadine topically into the lower fornix.  The lids may be 
scrubbed (if necessary) with cotton-tipped applicators soaked in 5% Betadine.  Place a 
sterile lid speculum.  Have the subject look up and apply a cotton-tipped applicator 
soaked in Betadine to the injection site.  Allow 30-60 seconds for the Betadine to dry 
prior to insert injection. 
4. Mark the injection site 3.5-4.0 mm posterior to the limbus in inferior quadrant with either 
calipers or the blunt end of a sterile tuberculin syringe. 
5. Open the foil pouch containing the applicator.  Retain the foil pouch with the patient’s 
source documents.  Prior to inserting the needle, the conjunctiva should be gently 
displaced so that after withdrawing the needle, the conjunctival and scleral needle entry 
sites will not align.  Insert the needle at the marked site up to the hub.  Once plunger is 
depressed fully and the insert has been delivered, remove the applicator. 
6. Administer 1-2 drops of topical antibiotic.  Remove the lid speculum. 
7. Perform indirect ophthalmoscopy to verify adequate central retinal artery perfusion, 
absence of any other complications, and to verify the placement of the insert. 
a. If the FAI insert is observed to be misplaced within the eye, please contact the 
unmasked monitor and sponsor immediately.  Administration of a second FAI insert 
within the study eye is not permitted.  
8. Discard the used applicator. 
9. Determine IOP [recorded as a mean of three measurements within 10 minutes of injection 
and at 60 minutes following the injection] 
10. For post-administration follow-up, prescribe a topical antibiotic for the subject to self-
administer 4 times per day for 3-5 days 
11. Contact the subject on the next day to follow up on the subject’s ocular condition and to 
identify any complaint and/or adverse event. 


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9.7.4. 
Sham Injection Procedure 
Subjects assigned to the sham injection control group will be prepared for injection in the same 
manner as the subjects in the FAI insert treatment group (steps 1-4 above) and will receive the 
same post-treatment evaluations and medications as the FAI insert group (steps 6-11 above).  
Only step 5 is different.  When the investigator opens the treatment packaging for a subject 
assigned to the sham injection control group, the package will contain a syringe with a blunt 
needle attached.  The sham injection will consist of pressing the blunt needle against the sclera of 
the eye with approximately the same pressure as would be used during the injection of a FAI 
insert. 
9.8. 
Criteria for FAI Insert Removal 
Investigators should consider removing the FAI insert if any of the following events occur: 
• Apparent intolerance to insert 
• Endophthalmitis  
• Partial extrusion or exposure of insert 
Based on prior human experience with Iluvien, a product virtually identical to the FAI insert 
(refer to the Investigator’s Brochure for more details), the likelihood that insert removal will 
become necessary is very small. 
9.9. 
Post-Treatment Visits and Long Term Follow-up 
Investigator 2 (masked investigator) will be responsible for all safety and efficacy procedures 
and assessments following Day 1. 
The subject will return to the study site on Day 7, 28 and Months 2, 3, 6, 9, 12, 18, 24, 30, and 
36, for a total duration of 36 months.  Subjects may be seen more frequently if medically 
indicated.  Table 4 provides descriptions of the ophthalmic assessment procedures to be 
performed, as indicated, at the scheduled visits.  All assessments are made for both eyes of all 
subjects. 
9.9.1. 
Post-Treatment Follow-up (Days 7 & 28) 
Assessments include: Vital signs (blood pressure and pulse rate after subject is in the sitting 
position for at least 5 minutes); Ophthalmic exam (BCVA, IOP, dilated indirect ophthalmoscopy 
and anterior, posterior and intermediate slit lamp examinations); OCT (Day 28); subjective 
ocular tolerability and discomfort assessment; concomitant meds and AEs. 
9.9.2. 
Long-Term Follow-up (Months 2, 3, 6, 9, 12, 18, 24, 30, & 36) 
Assessments include: Vital signs (blood pressure and pulse rate after subject is in the sitting 
position for at least 5 minutes); Ophthalmic exam (BCVA, IOP, dilated indirect ophthalmoscopy 
and anterior, posterior and intermediate slit lamp examinations); subjective ocular tolerability 
and discomfort assessment; visual field (Months 12, 24 and 36); OCT, pregnancy test (Months 
12, 24 and 36) and concomitant Meds and AEs. 


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9.10. 
Concomitant Medications/Procedures 
9.10.1. 
Tapering/Ending Systemic or Topical Uveitis Treatment Following Day1 
Subjects may be treated prior to entry in order to meet study inclusion criteria.  The objective of 
prior treatment is to obtain a relatively quiet eye prior to enrollment.  If a subject is receiving 
systemic corticosteroids or immunosuppressants, or topical steroids to control uveitis prior to 
study enrollment, that subject will have such treatment ended within three months following Day 
1, in a manner that follows the standard of care for ending the specific treatment.  For example, 
some systemic treatment regimens may be ended immediately, while others require a period of 
gradual dose reduction (tapering).  Systemic medications or topical steroids administered as part 
of gradual dose reduction are not considered prohibited medications. 
9.10.2. 
Prohibited Medications 
Other than the exceptions described in Section 9.10.1, Section 9.12 or in this section below, the 
following concomitant medications are not permitted during the study:  
• Oral, systemic, injectable, or topical steroids  
• Systemic immunosuppressants 
Systemic medications or topical steroids administered as part of gradual dose reduction 
(tapering), as described in Section 9.10.1, are not considered prohibited medications.  
Additionally, topical steroids administered as short term standard treatment following an ocular 
surgical procedure are not considered prohibited medications. 
It is advisable for the PI to discuss treatment with the Medical Monitor before administering any 
prohibited medication unless it is an emergency. 
9.10.3. 
IOP Reduction Therapy 
Pharmacologic treatment (eyedrops) of elevated IOP must be instituted whenever the IOP is >30 
mmHg, and may be instituted at lower IOP levels, at the discretion of investigator 2 and in 
accordance with the investigator’s standard of care.  Treatment may include referral to another 
ophthalmologist.  If IOP does not adequately respond to pharmacologic treatment, alternative 
treatment should be considered (laser, trabeculectomy).  The investigator should obtain 
information on the treatment administered by non-study ophthalmologists for inclusion in the 
study records. 
9.10.4. 
Cataract Removal and Other Elective Ocular Surgery  
Cataracts are recommended to be removed by extra-capsular extraction with 
phacoemulsification.  A cataract may be removed prior to a subject’s enrollment. 
Because of the importance of VA evaluations in this study, the timing of cataract removal or any 
elective surgery during the post-treatment follow-up period should be scheduled at least 4 weeks 
prior to any study visit involving VA assessment. 


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9.11. 
Unscheduled Follow-up Visits 
Additional examinations may be conducted as necessary to ensure the safety and well-being of 
subjects during the study period.  Electronic case report forms (eCRFs) should be completed for 
each unscheduled visit or test that the subject completes. 
9.12. 
Treatment of Recurrences of Uveitis 
In the event of a uveitis recurrence in either eye (defined as an “Endpoint”), peri-ocular or 
intraocular corticosteroid injections, or topical medications should be administered as first line 
local therapy, in accordance with the protocol.  Investigators should consider treatment with 
topical steroids as first line therapy for a recurrence that involves only an increase in anterior 
chamber cells with no increase in vitreous opacity.  Systemic immunosuppressants or systemic 
steroids should be used only if local therapy fails. 
Subjects who experience a recurrence of uveitis will continue participation in the study.  Once 
the subject’s recurrence is controlled, the treatment regimen (local or systemic therapy) will be 
ended in a manner that follows the standard of care for ending the specific treatment regimen. 
Details of each recurrence and its treatment will be documented in the eCRF. 
9.13. 
Description of Procedures 
Refer to Table 4 and the appendices (Sections 18, 19, and 20) for more details. 
9.13.1. 
Slit Lamp Examination 
Slit lamp examination should be performed using the investigator’s standard procedure.  This 
procedure should be the same for all subjects examined at the site and use the same equipment.  
Observations should be made to indicate the absence or presence of findings for conjunctiva, 
cornea, iris, and anterior and posterior chambers.  All findings are to be documented in the 
source documentation and the appropriate eCRF. 
9.13.2. 
Dilated Indirect Ophthalmoscopy 
Dilated indirect ophthalmoscopy should be performed as part of each ophthalmic examination.  
This procedure should be the same for all subjects examined at the site and use the same 
equipment.  All findings are to be documented in the source documentation and the appropriate 
eCRF. 
9.13.3. 
Visual Acuity 
BCVA will be measured according to the standard procedure developed for ETDRS at 4 meters 
or 3 meters if the electronic (E)-ETDRS system is employed.  Corrected-distance VA is to be 
reported as number of letters read correctly by the subject.  The details of refraction and VA 
determination procedures are provided in Section 18. 
9.13.4. 
OCT 
Optical coherence tomography (OCT) will be performed; Cirrus or Spectralis instruments are 
preferred. 


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9.13.5. 
Intraocular Pressure 
Applanation tonometry (preferably Goldmann) will be used for IOP measurements where an 
average of 3 measurements will be recorded using the investigator’s standard procedure. 
9.13.6. 
Subjective Ocular Tolerability and Discomfort Assessment 
Refer to Appendix 3 (Section 20) for details: 
• Subjective ocular discomfort grading 
• Subjective tolerability using visual analog scale for pain 
9.14. 
Laboratory Testing 
Clinical laboratory testing will include: 
• Hematology (standard tests) 
• ESR 
• electrolytes: sodium; potassium; chloride; calcium; bicarbonate/CO2 
• renal function: serum creatinine, BUN 
• hepatic function: serum bilirubin, alkaline phosphatase, SGOT/AST, SGPT/ALT, 
total albumin, total protein 
• HIV and syphilis serology testing 
• Screening test for latent mycobacterium tuberculosis (TB) infection 
• Urinalysis (standard tests) 
• Urine pregnancy test (for females of childbearing potential) 
9.15. 
Protocol Deviations 
The investigator will not deviate from the requirements from this protocol without prior approval 
from pSivida Corp. unless necessitated by a medical emergency (i.e., those that impact subject 
safety or the validity of the study).  All other significant changes to the protocol will be made by 
pSivida Corp. as a protocol amendment and approved by IRB/EC and the appropriate regulatory 
authority prior to implementation. 
9.16. 
Study Termination or Suspension 
If the trial is prematurely terminated or suspended for any reason, the investigator/institution 
should promptly inform the trial subjects, should assure appropriate therapy and follow-up for 
the subjects, and, where required by the applicable regulatory requirement(s), should inform the 
regulatory authority. 
In addition, if the investigator terminates or suspends a trial without prior agreement of pSivida, 
the investigator should inform the institution where applicable, and the investigator/institution 
should promptly inform pSivida and the IRB/IEC, and should provide pSivida and the IRB/IEC a 
detailed written explanation of the termination or suspension. 


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If pSivida terminates or suspends this trial, the investigator should promptly inform the 
institution where applicable and the investigator/institution should promptly inform the IRB/IEC 
and provide the IRB/IEC a detailed written explanation of the termination or suspension. 
If the IRB/IEC terminates or suspends its approval/favorable opinion of this trial, the investigator 
should inform the institution where applicable and the investigator/institution should promptly 
notify pSivida and provide pSivida with a detailed written explanation of the termination or 
suspension. 
9.17. 
Subject Withdrawal Criteria 
Subjects have the right to withdraw from the study at any time, for any reason, without 
jeopardizing their medical care.  The following are examples of criteria for considering 
withdrawal from this study: 
• Withdrawal of subject consent; or 
• Intercurrent illness including death that prevents continuation of regular follow-up 
visits 
All subjects will be followed for safety through their final visit unless withdrawn from the study 
for the above reasons. 
The investigator, IRB/EC and pSivida Corp. also have the right to withdraw subjects from the 
study for the following reasons: when continuation may jeopardize the health of the subject, 
protocol violations, AEs or concurrent conditions, administrative or other reasons. 
Subjects who withdraw for any reason from the study following randomization and 
administration of study treatment (FAI insert or sham injection) will not be replaced.  All 
randomized subjects will be followed for as long as they agree to return for visits. 
10. 
INVESTIGATIONAL MATERIALS 
10.1. 
Test Article  
10.1.1. 
Description 
The FAI insert is an injectable intravitreal sustained-release FA delivery system preloaded into 
an injection device.  Each insert contains a drug core of FA as the active ingredient within a 
cylindrical polyimide polymer tube 3.5 mm long with an external diameter of 0.37 mm.  One end 
of the tube is capped with an impermeable polymer (silicone adhesive); the other end is capped 
with a permeable polyvinyl alcohol membrane.  FA release occurs through the permeable end of 
the cylinder.  Each FAI insert contains 0.18 mg FA and delivers FA into the vitreous humor for 
36 months, as demonstrated in a clinical pharmacokinetics study of Iluvien (Campochiaro 2012).  In 
vitro data demonstrate that initial FA release occurs at a rate of approximately 0.2 μg FA/day, 
gradually decreasing over three years to a rate of approximately 0.1 μg FA/day.  The FAI insert 
is designed to be injected through the pars plana into the vitreous. 


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10.1.2. 
FAI Insert Packaging and Labeling 
FAI inserts will be supplied as individual finished products in primary, secondary and tertiary 
packaging.  The primary packaging is the applicator, which includes a 25 g needle that is 
attached to the applicator.  The FAI insert is pre-loaded in the applicator, which is designed to 
facilitate precise placement of the FAI insert to an exact depth in the vitreous.  The pre-loaded 
applicator is placed into the secondary packaging, a 2.5” x 15” foil chevron pouch and heat-
sealed.  Lastly, the foil pouch is placed into a 3.5” x 18” Tyvek chevron pouch.  The outer 
chevron pouch will be labeled as investigational drug in accordance with applicable regulations.  
The assembled units are subsequently sterilized by gamma irradiation, resulting in the FAI insert 
Finished Product, a sterile, single-use product. 
10.1.3. 
Investigational Product Storage 
Investigational product must be stored at controlled room temperature in a secured location 
accessible only to study personnel. 
10.2. 
Sham Injector  
10.2.1. 
Description 
The sham applicator is an empty 1 ml syringe attached to a blunt needle; it does not contain a 
FAI insert. 
10.2.2. 
Sham Injector Packaging and Labeling 
Sham injectors will be supplied as individual finished products in primary, secondary and tertiary 
packaging.  The primary packaging is the sham applicator, which includes a blunt needle.  The 
sham applicator is placed into the secondary packaging, a 2.5” x 15” foil chevron pouch and 
heat-sealed.  Lastly, the foil pouch is placed into a 3.5” x 18” Tyvek chevron pouch.  The outer 
chevron pouch will be labeled for investigational use in accordance with applicable regulations.  
The assembled units are subsequently sterilized by gamma irradiation, resulting in the sham 
injector, a sterile, single-use product. 
10.2.3. 
Sham Injector / Finished Product Storage 
Sham injector / Finished Product units must be stored in a secure, locked location accessible only 
to authorized study personnel, and maintained at controlled room temperature of 15°-25ºC (59-
77ºF). 
10.3. 
Supply and Accountability of Materials 
pSivida Corp. will supply the Finished Product units (FAI insert or sham injector) for this study.  
A log will be maintained at each study site, showing the ID number of the subject to whom each 
unit is dispensed, the date and who dispensed the Finished Product unit.  Sufficient Finished 
Product units will be supplied to each investigative site to allow replacement, as necessary, of 
any damaged unit.  The investigator must maintain records of all shipments of study materials 
and account for all used and unused materials.  All unused and damaged study materials must be 
returned to pSivida Corp. or destroyed on site, with an accounting of all materials supplied, used, 
and returned, and an explanation for any discrepancies. 


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11. 
ASSESSMENT OF SAFETY  
11.1. 
Adverse and Serious Adverse Events 
The following are specific definitions of terms guided by the International Conference on 
Harmonization (ICH) Guidelines for Good Clinical Practice (GCP) and the U.S. Code of Federal 
Regulations (CFR) that apply to this section. 
11.1.1. 
Adverse Events (AE) 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) 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, for example), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational product. 
11.1.2. 
Serious Adverse Event (SAE) 
A SAE is any untoward medical occurrence that at any dose:  
• Results in death  
• Is life-threatening (The term “life-threatening” 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 were more intense.)  
• Requires in subject hospitalization or prolongs existing hospitalization  
• Results in persistent or significant disability / incapacity  
• Is a congenital anomaly / birth defect  
• May jeopardize the subject or may require intervention to prevent one of the 
outcomes listed above.  Medical and scientific judgment should be exercised in 
deciding if these events should be considered serious.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse.  
The following hospitalizations are not considered SAEs: 
• A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered "important medical event" or life threatening 
event) 
• Elective surgery, planned prior to signing consent 
• Admissions as per protocol for a planned medical/surgical procedure 
• Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy) 


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• Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study.  Appropriate documentation is required in these 
cases 
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative) 
11.1.3. 
Ocular Events  
11.1.3.1. Ocular adverse events 
The following ocular events will be considered adverse events for the purposes of this trial:  
• decrease in visual acuity of at least ≥ 15 letters or ≥ 3 lines from the previous 
measurement of visual acuity 
• moderate or severe (grade 3 or 4) ocular findings compared to the last ophthalmic 
examination 
• worsening of > 2 steps in anterior chamber cell count or vitreous haze, compared to 
the last ophthalmic examination 
• increase in IOP of > 10 mmHg at two visits at least 1 week apart or an increase in 
IOP to > 25 mmHg 
11.1.3.2. Sight-Threatening Ocular Events Defined as SAEs in This Study 
In addition to the standard SAE categories described above, this study defines these additional 
ocular events as SAEs: 
• An AE which causes a decrease in visual acuity of ≥ 30 letters or ≥ 6 lines from the 
most recent previous measurement of visual acuity, lasting more than 1 hour 
• An AE which causes a decrease in visual acuity to light perception or worse, lasting 
more than 1 hour 
• An AE which requires surgical intervention (e.g., conventional surgery, vitreous tap 
or biopsy with intravitreal injection of anti-infectives, or laser or retinal cryopexy 
with gas) to prevent permanent loss of sight 
• An AE which is associated with severe intraocular inflammation (i.e., 4.0 anterior 
chamber cell score, 4+ flare or 4+ vitritis) 
• Two consecutive IOP measurements of 30 mmHg or higher taken at least 72 hours 
apart when a subject is already being treated with two glaucoma medications  
• An IOP < 6 mmHg requiring medical intervention 
• An AE which in the opinion of the investigator requires medical or surgical 
intervention to prevent permanent loss of sight 


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11.1.4. 
Laboratory Test Abnormalities 
All laboratory test values captured as part of the study, including screening, should be recorded 
on the appropriate laboratory test results pages of the eCRF. 
In addition, the following laboratory abnormalities should also be captured on the nonserious AE 
CRF page (paper or electronic) or SAE paper CRF page as appropriate: 
• Any laboratory test result that is clinically significant or meets the definition of an 
SAE 
• Any laboratory abnormality that required the subject to receive specific corrective 
therapy. 
It is expected that wherever possible, the clinical, rather than the laboratory term would be used 
by the reporting investigator (e.g., anemia versus low hemoglobin value). 
11.1.4.1. Pregnancy 
Sexually active women of child bearing potential (WOCBP) must be encouraged to use an 
effective method of birth control during the course of the study, in a manner such that risk of 
failure is minimized. 
All WOCBP MUST have a negative urine pregnancy test within 48 hours prior to receiving the 
investigational product.  If the pregnancy test is positive, the subject must not receive the 
investigational product and must not be enrolled in the study. 
Pregnancy testing must also be performed on all WOCBP throughout the study as specified and 
the results of all pregnancy tests (positive or negative) recorded on the eCRF. 
In addition, all WOCBP should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
11.2. 
Adverse Event Assessment 
11.2.1. 
Relationship to Study Treatment 
The study treatment relationship to each AE should be determined by the investigator using these 
explanations: 
Unrelated:  Evidence indicates no plausible direct relationship to the study medication, 
device or procedure, or there is a reasonable causal relationship between noninvestigational 
product, concurrent disease, or circumstance and the AE. 
Possibly Related:  There is reasonable causal relationship between the investigational 
product, device or procedure and the AE.  Suggests that the association of the event with the 
study medication, device, or procedure is unknown; however, the adverse event is not 
reasonably supported by other conditions. 
Probably Related:  Suggests that a reasonable temporal sequence of the event with 
medication administration, device usage or the index procedure exists and, based upon the 


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investigator's clinical experience, the association of the event with study medication, device 
or procedure is likely.  
The Investigator will make the determination of relationship to the investigational product for 
each AE (Unrelated, Possibly Related or Probably Related).  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, device or procedure.  If no valid reason exists for 
suggesting a relationship, then the AE should be classified as “unrelated.” 
If there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the AE, then the AE 
should be considered as related. 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” the event will be considered to be related to the investigational product 
for the purposes of expedited regulatory reporting. 
11.2.2. 
Severity 
AE severity is defined as a qualitative assessment of the degree of intensity of an AE as 
determined by the investigator or reported to him/her by the subject.  The assessment of severity 
is made irrespective of test article relationship or seriousness of the event and should be 
evaluated according of the following scale: 
Mild:  Awareness of event but easily tolerated.  Usually transient, requiring no special 
treatment, and does not interfere with the subject’s daily activities. 
Moderate:  Discomfort enough to cause some interference with usual activity.  Traditionally 
introduces a low level of inconvenience or concern to the subject and may interfere with 
daily activities, but are usually relieved by simple therapeutic measures. 
Severe:  Causes an interruption of the subject’s usual daily activity and traditionally requires 
systemic drug therapy or other treatment. 
11.3. 
Recording of Adverse Events 
Changes in a chronic condition or disease, part of the medical history of the patient, that are 
consistent with natural disease progression are not to be considered as AEs and should not be 
recorded as such.  Medical conditions or diseases present before a subject starts study treatment 
are only considered AEs if they worsen after the start of the study treatment. 
Adverse events can be spontaneously reported or elicited at each study visit through open-ended 
questioning, examination, or evaluation of a subject.  (In order to prevent reporting bias, subjects 
should not be questioned regarding the specific occurrence of one or more AEs). 
The investigator will record all AEs in eCRF.  If known, the diagnosis of the underlying illness 
or disorder should be recorded, rather than its individual symptoms. 
The following information should be captured for all AEs: onset and end date, severity, 
seriousness, relationship to investigational product, action taken and treatment required and 
outcome.  If treatment for the AE was administered, it should be recorded on the appropriate 
eCRF page. 


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Completion of supplemental eCRF pages may be requested for AEs and/or laboratory 
abnormalities that are reported/identified during the course of the study. 
The investigator will take or organize all appropriate and necessary therapeutic measures 
required for resolution of the adverse event.  Any medication necessary for the treatment of an 
adverse event must be recorded on the concomitant medication case report form.  If more than 
one distinct AE occurs, each event should be recorded separately. 
11.4. 
Adverse Event Reporting 
All subjects enrolled in the study will be evaluated for adverse events.  For the individual 
subjects, adverse events will be collected from Day 1 until study completion. 
All AEs will be evaluated from their onset until resolution, stabilization, last day of participation 
in the study of the patient or the last day of the study, whichever is first. 
Adverse events that continue after the subject’s discontinuation or completion of the study will 
be followed until their medical outcomes are determined or until no further change in the 
condition is expected.  The event and outcome will be reported in writing by the investigator to 
pSivida.  The investigator shall supply the sponsor and IRB/EC with any additional requested 
information, notably for reported deaths of subjects. 
11.4.1. 
Reporting of Serious Adverse Event  
All SAEs that occur during the course of the study, including death, must be reported within 24 
hours following the site’s knowledge of the SAE and recorded on the Serious Adverse Event 
Page of the eCRF (or use a back-up paper form if electronic system is not functioning). 
Minimal information to be provided includes: 
• Identification of the study 
• Identification of the initial reporter 
• Patient identification number  
• Event term 
• Date of onset of the event  
• Severity criteria of the event  
• Reporting criteria 
• Narrative description of the event  
• Outcome if known 
• Causal relationship to the investigational medication, device and procedure 
• Additional and follow-up information as requested by the medical monitor 
 


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11.4.2. 
Reporting of Pregnancy 
To ensure patient safety, each pregnancy in a female patient must be reported by the investigator 
to pSivida Corp., within 24 hours of learning of its occurrence.  The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal or 
newborn complications. 
Pregnancy should be recorded on a Pregnancy Report Page of the eCRF.  Pregnancy follow-up 
should be recorded on the paper Pregnancy Report form and should include an assessment of the 
possible relationship to the study drug of any pregnancy outcome.  Any SAE experienced during 
pregnancy must be reported as appropriate. 
If any male subject's partner becomes or is found to be pregnant during the male subject's 
treatment with the investigational product, the investigator must submit this information to 
pSivida on a Pregnancy Report Form as described above. 
11.4.3. 
Other Safety Considerations 
Any significant changes noted during interim or final physical examinations, electrocardiograms, 
x-rays, and any other potential safety assessments, whether or not these procedures are required 
by the protocol, should also be recorded on the appropriate nonserious AE page of the eCRF or 
SAE eCRF page. 
The SAE(s) is to be reported by the Investigator within 24 hours of awareness of the event via 
eCRF.  
Sites in Europe, Asia-Pacific, Africa, and the Middle East will contact: 
PPD Medical Support Center 
Telephone:  
+44 1223 374 240 
Telefax: 
 
+44 1223 374 102 
 
Sites in North America will contact: 
PPD Medical Support Center 
Telephone: 
800-201-8725 
Telefax: 
 
888-529-3580 
11.5. 
Expedited Safety Reporting 
Adverse drug reactions (ADRs) that are suspected, serious, and unexpected are subject to 
expedited reporting.  Reports which add significant information on specificity or severity of a 
known, already documented serious ADR constitute unexpected events.  For example, an event 
more specific or more severe than described in the protocol under safety assessments would be 
considered "unexpected".  Specific examples would be (a) acute renal failure as a labeled ADR 
with a subsequent new report of interstitial nephritis and (b) hepatitis with a first report of 
fulminant hepatitis. 
The purpose of expedited reporting is to make regulators, investigators, and other appropriate 
people aware of new, important information about serious adverse product reactions.  Therefore, 
such reporting will generally involve events previously unobserved or undocumented.  


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Accordingly, expedited reporting will ordinarily be inappropriate for adverse drug reactions that 
are serious but expected. 
In accordance with local regulations, pSivida will notify investigators of all SAEs that are 
suspected (probably or possibly related to the investigational product) and unexpected (i.e., not 
previously described in the Investigator Brochure). 
Investigator notification of these events will be in the form of an expedited safety report (ExSR). 
Other important findings which may be reported by the sponsor as an ExSR include: increased 
frequency of a clinically significant expected SAE, an SAE considered associated with study 
procedures that could modify the conduct of the study, lack of efficacy that poses significant 
hazard to study subjects, clinically significant safety finding from a nonclinical (e.g., animal) 
study, important safety recommendations from a study data monitoring committee, or sponsor 
decision to end or temporarily halt a clinical study for safety reasons. 
Upon receiving an ExSR from pSivida, the investigator must review and retain the ExSR with 
the Investigator Brochure.  Where required by local regulations or when there is a central 
IRB/IEC for the study, the sponsor will submit the ExSR to the appropriate IRB/IEC.  The 
investigator and IRB/IEC will determine if the informed consent requires revision.  The 
investigator should also comply with the IRB/IEC procedures for reporting any other safety 
information. 


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12. 
REPORTING OF TECHNICAL COMPLAINTS 
Technical complaints include quality complaints reported in writing, electronically, or orally 
involving the use or attempted use of this product that identify any defects in the product (e.g., 
failure of the applicator to deliver the FAI insert), or dissatisfaction with any other 
characteristic(s) of the drug product (labeling, packaging, etc.). 
Any technical complaint should be reported by telefax to pSivida Corp. (1-617-926-5050), 
Attention: Marty Nazzaro, within 24 hours.  
The complaint report should include the following information:  
• Product identification number 
• Investigator name, study center name, and contact number 
• Date the complaint occurred  
• Brief description of the complaint  
• Subject involved? (yes or no); if yes, were any AEs associated with the complaint? 
(yes or no), (If an AE is associated with the complaint, refer to Section 11.)  
The drug container which initiated the complaint should be returned to pSivida Corp. (address 
below) for analysis.  
Attention: Marty Nazzaro or Gerard Riedel 
pSivida Corp. 
480 Pleasant Street 
Watertown, MA 02472 USA 
Any complaint about an investigational product must be reported regardless of whether the 
defect or deficiency had any effect on a subject or on study personnel. 


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13. 
ASSESSMENT OF EFFICACY 
13.1. 
Primary Efficacy Endpoint 
The Primary Efficacy Endpoint is defined as the proportion of subjects who have a recurrence of 
uveitis in the study eye within 6 months following treatment.  Recurrence is defined as: 
• A > 2 step increase in the number of cells in the anterior chamber per high powered 
field (1.6 X using a 1-mm beam) (Hogan 1959), compared to baseline or any visit 
time point prior to Month 6 
OR 
• An increase in the vitreous haze of > 2 steps (Nussenblatt 1985), compared to 
baseline or any visit time point prior to Month 6 
OR 
• A deterioration in visual acuity of at least 15 letters BCVA, compared to baseline or 
any visit time point prior to Month 6 
Any criterion used to define recurrence must be attributable only to noninfectious uveitis.  To 
prevent post-procedural inflammatory reactions from being reported as uveitis recurrences, 
assessments for recurrence of uveitis begin after study Day 7 visit. 
Refer to Appendix 2 (Section 19) for additional information. 
13.2. 
Exploratory Efficacy Endpoints:  
Exploratory endpoints include: 
• Proportion of subjects who have a recurrence of uveitis in the study eye within 12 
months or 36 months 
• Proportion of subjects who have a recurrence of uveitis in the fellow eye (within 6 
months, 12 months or 36 months) 
• Mean change from baseline in BCVA letter score in the study eye (at 6 months, 12 
months or 36 months) 
• Number of recurrences of uveitis (within 6 months, 12 months or 36 months) 
• Time to recurrence of uveitis (within 6 months, 12 months or 36 months) 
• Number of adjunctive treatments required to treat recurrences of uveitis (within 6 
months, 12 months or 36 months) 
• Resolution of macular edema, as measured by OCT imaging (at 6 months, 12 months 
or 36 months) 


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14. 
 DATA ANALYSES 
14.1. 
Sample Size 
A two group continuity corrected Chi-square test with a 0.05 two-sided significance level will 
have 89% power to detect the difference between a Sham group recurrence free rate of 0.600 and 
a FAI treated group recurrence free rate of 0.880 (odds ratio of 0.205) when the sample sizes are 
40 and 80, respectively (a total sample size of 120). 
14.2. 
Study Populations  
14.2.1. 
Intent to Treat (ITT) Population 
The ITT population will include all subjects randomized into the study; analyzed as randomized.  
14.2.2. 
Safety Population 
The safety population will include all subjects randomized into the study; analyzed as treated. 
14.2.3. 
Per Protocol (PP) Population 
The per protocol (PP) population will be defined separately for the month 6, month 12 and 
month 36 analyses and will exclude all subjects in the ITT population who meet any of the 
following criteria: 
• Received systemic treatment for recurrence of uveitis in fellow eye 
• Received an imputed endpoint at the 6 month (or the 12 month or the 36 month) 
endpoint of the study 
• Failed screening, without exemption, but received FAI insert 
• Had a major protocol deviation  
(Protocol deviations, both major and minor, will be defined prior to database lock) 
14.3. 
Analyses  
14.3.1. 
Analyses of Demographic and Baseline Data  
Demographic and baseline characteristics of the ITT population will be presented in tabular 
summaries by treatment group.  Continuous variables will be summarized using the mean, 
standard deviation, median, minimum and maximum; categorical variables will be summarized 
using counts and percentages of subjects in each category. 
14.3.2. 
Subject Disposition and Exposure 
Tabulation of study completion and premature study termination along with reasons for 
termination will be provided by treatment group.  Duration of study participation and insert 
duration will also be tabulated. 
14.3.3. 
Schedule of Analyses of Efficacy and Safety 
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1. After all subjects have completed the Month 6 visit (or have been discontinued from the 
study prior to this visit).  The primary analysis of efficacy will occur at the Month 6 time 
point. 
2. After all subjects have completed the Month 12 visit (or have been discontinued from the 
study prior to this visit). 
3. After all subjects have completed the Month 36 visit (or have been discontinued from the 
study prior to this visit). 
14.3.4. 
Analyses of Efficacy 
Efficacy analyses will be performed on both the ITT population and the PP population, at 6, 12 
and 36 months.  All primary and exploratory efficacy endpoints will be analyzed using the ITT 
population and the PP population.  Descriptive statistics will be used in all exploratory efficacy 
analyses.  The ITT data set analyses will be considered primary; the PP data set analyses will be 
considered supportive of the primary analyses. 
14.3.4.1. Primary Efficacy Variable and Analysis  
The primary efficacy analysis will be performed on the ITT population at 6 months and will 
compare the proportion of subjects, in the treatment and control groups, who do not have a 
recurrence of uveitis in the study eye (as defined in the protocol) in the 6 months following 
Day 1.  To prevent post-procedural inflammatory reactions from being reported as uveitis 
recurrences, assessments for recurrence of uveitis will begin after study Day 7 visit. 
The primary efficacy analysis will be conducted after all subjects in the study have completed 6 
months of treatment or have discontinued study participation.  
A continuity corrected Chi-square analysis will be used to assess the statistical significance of a 
difference between study groups in the primary efficacy analysis. 
Mathematically stated: 
H0: 6 Month Recurrence Free Rate FAI = 6 Month Recurrence Free Rate Sham 
H1: 6 Month Recurrence Free Rate FAI ≠ 6 Month Recurrence Free Rate Sham 
14.3.4.2. Data Imputation 
Data for the primary outcome only (recurrence of uveitis in the study eye) will be imputed using 
a straightforward method: 
• A subject who has not previously experienced a recurrence and does not complete the 
required eye examinations at Month 6 (or Month 12 or 36 for the Month 12 or 36 
analyses, respectively) for any reason will be considered as having a recurrence. 
• A subject who has not previously experienced a recurrence and takes a prohibited 
systemic concomitant medication as defined in Section 9.10.2 any time during the 
study prior to Month 6 (or Month 12 or 36 for the Month 12 or 36 analyses, 
respectively) will be considered as having a recurrence.   


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• A subject who has not previously experienced a recurrence and takes a prohibited 
local concomitant medication in the study eye as defined in Section 9.10.2 any time 
during the study prior to Month 6 (or Month 12 or 36 for the Month 12 or 36 
analyses, respectively) will be considered as having a recurrence. 
Systemic medications and topical steroids administered as part of gradual dose reduction 
(tapering) (as described in Section 9.10.1) will not be considered prohibited medications. 
Additionally, topical steroids administered as short term standard treatment following an ocular 
surgical procedure will not be considered prohibited medications (as described in  
Section 9.10.2). 
14.3.4.3. Sensitivity Analyses for the Primary Outcome at 6, 12 and 36 Months 
In addition to the conservative imputation for the primary efficacy outcome detailed in  
Section 14.3.4.2, the following sensitivity analyses of the primary efficacy outcome will be 
separately performed at 6, 12 and 36 months. 
• The primary outcome will be imputed exactly as in Section 14.3.4.2 except that a 
subject imputed as having a recurrence because of missing eye examinations at 
Month 6 (or Month 12 or Month 36) for any reason will be considered as NOT having 
a recurrence. 
• A “tipping point” analysis will be performed.  This analysis will begin by using the 
following imputations associated with missing required eye examinations at Month 6 
(or Month 12 or Month 36) for any reason: FAI insert treated subjects will be 
considered as having a recurrence, and sham treated subjects will be considered as 
NOT having a recurrence.  The analysis will proceed, one imputed FAI insert treated 
subject at a time, assuming that this given subject will be considered as NOT having a 
recurrence.  All other imputations stated in Section 14.3.4.2 will be performed during 
this “tipping point” analysis.  Inferential analysis employing the primary analysis will 
be performed at each step of the “tipping point” assessment. 
Additionally, for missing data due to other reasons, sensitivity analyses will be conducted by 
using multiple imputation methods.  Further details will be provided in the statistical analyses 
plan (SAP).  
14.3.4.4. Exploratory Analyses  
The following endpoints will be analyzed for the ITT and PP populations employing descriptive 
statistics only:  
• Proportion of subjects in each treatment group who have a recurrence of uveitis in the 
study eye within 12 months and 36 months 
• Proportion of subjects in each treatment group who have a recurrence of uveitis in the 
fellow eye (within 6 months, 12 months and within 36 months) 
• Mean change from baseline in BCVA letter score in the study eye in each treatment 
group (at 6 months,12 months and 36 months) 


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• Number of recurrences of uveitis in each treatment group (within 6 months,12 months 
and within 36 months) 
• Time to recurrence of uveitis in each treatment group (within 6 months,12 months 
and within 36 months) 
• Number of adjunctive treatments required to treat recurrences of uveitis in each 
treatment group (within 6 months,12 months and within 36 months) 
• Resolution of macular edema, as measured by OCT imaging (at 6 months,12 months 
and 36 months) 
14.3.4.5. Subgroup Analyses  
Subgroup analyses will be performed on the primary efficacy variable.  Analyses will be 
performed to determine the treatment effect within specific subgroups of interest, and to 
determine if the treatment effect is consistent across different subgroup levels.  Subgroups will 
be defined on the basis of baseline characteristics, including severity of edema, duration of 
disease, lens status, intraocular pressure, presence/absence of vitrectomy, and BCVA.  Further 
details will be provided in the statistical analyses plan (SAP).  
14.3.5. 
Analyses of Safety 
Safety analyses will be performed on the safety population at 6, 12 and 36 months.  Subjects 
randomized but not receiving treatment will have all safety data listed only but will not be 
included in safety tabulations.  Descriptive statistics will be provided for all adverse events.  
Frequency counts and percentage of subjects within each category will be provided for 
categorical data.  Treatment Emergent Adverse Events (TEAEs; those that occurred on the day 
or after treatment) will be coded to a corresponding preferred term from the MedDRA coding 
dictionary. 
Ocular safety will be assessed by evaluating ocular TEAEs, visual acuity, IOP, concomitant 
medications, and slit lamp / dilated indirect ophthalmoscopy exams.  Systemic safety will be 
assessed by evaluating all TEAEs, vital signs, concomitant medications and clinical laboratory 
tests by treatment group. 
Adverse events will be summarized by presenting the number and percentage of subjects having 
at least one occurrence of any TEAE during the study, having at least one occurrence of an 
TEAE within each system organ class, and having at least one occurrence of each individual 
TEAE (preferred term) in each treatment group.  Occurrence of TEAEs using MedDRA 
preferred term, SOC, by severity and relationship will be provided by treatment group.  If a 
patient experiences multiple events that map to a single preferred term, the greatest severity and 
strongest investigator assessment of relation to the investigational product will be assigned to the 
SOC and preferred term for the appropriate summaries.   
Treatment-emergent serious adverse events (SAEs) and TEAEs related to FAI treatment will be 
provided by preferred term, SOC and severity for each treatment group.  Again, if a patient 
experiences multiple events that map to a single preferred term, the greatest severity and 
strongest investigator assessment of relation to the investigational product will be assigned to the 


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SOC and preferred term for the appropriate summaries.  Adverse events leading to study 
discontinuation and any deaths will be listed. 
Vital signs will be presented using descriptive statistics by visit in each treatment group.  
Concomitant medication will be summarized by presenting the number and percentage of 
patients receiving each medication by term and treatment after coding with WHO-Drug 
Dictionary terms.  Laboratories assessments will be presented by descriptive statistics. 
15. 
ADMINISTRATIVE AND REGULATORY CONSIDERATIONS 
15.1. 
Quality Control and Quality Assurance 
pSivida Corp. employees and/or their contracted representatives utilize SOPs designed to ensure 
that research procedures and documentation are consistently conducted/prepared to the highest 
quality standards.  These SOPs also require compliance with Health Authority regulations and 
GCP guidance. 
A Quality Assurance audit may be conducted by pSivida Corp. or a designee at any time during 
or after completion of this study.  The investigator will be given adequate notice if he/she is 
selected for an audit.  The audit will include, but is not limited to, a review of all ICFs, a review 
of eCRFs, associated source documents and medical records, a review of regulatory 
documentation, an assessment of study conduct and protocol compliance, and a review of the 
investigational drug accountability.  At the conclusion of an audit, the auditor will conduct a 
brief meeting with the investigator to review the audit findings. 
15.2. 
Institutional Review Boards / Independent Ethics Committee 
Prior to the initiation of the study, the protocol, the ICF and the Investigator’s Brochure will be 
submitted to the IRB/EC for approval.  By signing the "Statement of Investigator" form (FDA 
form 1572), the investigator is assuring that an IRB/EC which complies with the requirements 
set forth in 21 CFR Part 56 will be responsible for the initial and continuing review of the 
proposed clinical study.  A copy of the IRB/EC approval letter for the protocol, and the informed 
consent, as well as the protocol signature page must be submitted to pSivida Corp. or its designee 
prior to release of investigational supplies to the study site.  The approval letter must refer to the 
specific protocol and informed consent form.  The study site must maintain an accurate and 
complete record of all reports, documents and other submissions made to the IRB/EC concerning 
this protocol.  A list of the IRB/EC members, their titles or occupations, and their institutional 
affiliation, or an IRB/EC assurance number must be provided to pSivida Corp. or its designee 
prior to release of study supplies. 
FDA/relevant health authority regulations require that all advertisements for subject recruitment 
be approved by an IRB/EC prior to implementation.  The complete text and format must be 
submitted to pSivida Corp. or designee for approval prior to IRB/EC submission. 
The investigator is responsible for notifying the IRB/EC of any SAEs.  A copy of the notification 
must be forwarded to pSivida Corp. or its designee. 
Status reports must be submitted to the IRB/EC at least once a year (or more frequently as 
required by the IRB/EC) and the IRB/EC must be notified of study completion or termination.   


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A final report must be provided to the IRB/EC and pSivida Corp. within 6 months of study 
completion or termination.  This report should include: any protocol deviations, the number of 
subjects evaluated, the number of subjects who withdrew or were withdrawn and the reasons for 
withdrawal, any significant AEs and the investigator's summation of the study. 
15.3. 
Informed Consent Process 
It is the responsibility of the investigator to inform each subject, prior to the screening 
evaluation, of the purpose of this clinical trial, including possible risks and benefits and 
document the informed consent process in the subject’s chart.  Prior to entry into the study or 
initiation of any study-related procedures, the subject must read, sign and date the IRB/EC 
approved ICF.  The person executing the consent must also sign and date the final consent form 
page.  . One or two signed originals of the ICF will be prepared, in accordance with applicable 
local requirements.  A signed original copy will be retained with the subject records, and either a 
copy of the signed original or the other signed original of the ICF will be given to the subject, in 
accordance with applicable local requirements. 
15.4. 
Source Documentation 
The investigator must maintain adequate and accurate source documents upon which eCRFs for 
each subject are based.  These documents are to be separate and distinct from eCRFs, except for 
cases in which pSivida Corp. has predetermined that direct data entry into specified pages of the 
subject’s eCRF is appropriate.  The investigator must allow access to the source documents by 
representatives of pSivida Corp. and regulatory authorities as needed.  These records should 
include detailed notes on: 
• The date the subject entered the study, study protocol number and name of the 
sponsor. 
• The oral and written communication with the subject regarding the study treatment 
(including the risks and benefits of the study).  The date of informed consent must be 
recorded in the source documentation. 
• The subject’s medical history prior to participation in the study and evidence that the 
subject meets study eligibility requirements 
• The subject’s basic identifying information, such as demographics, that links the 
subject’s source documents with the eCRFs 
• The dates of all study related subject visits. 
• The results of all diagnostic tests performed, diagnoses made, therapy provided, and 
any other data on the condition of the subject 
• The subject’s exposure to study treatment, documentation of study treatment 
accountability 
• All AEs 
• The subject’s exposure to any concomitant therapy (including start and stop dates, 
route of administration, and dosage) 


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• All relevant observations and data on the condition of the subject throughout the 
study 
• The date when subject exited the study and a notation as whether the subject 
competed the study or was discontinued, included the reason for discontinuation. 
15.5. 
Electronic Case Report Forms 
All study data must be incorporated in the corresponding electronic case report forms.  The 
investigator will be responsible for recording all data in the eCRFs.   
Data from clinical laboratory reports, etc. will be incorporated into the eCRFs either by direct 
transcription into appropriate eCRF pages or by inclusion of photocopies of these reports with 
printouts of the appropriate eCRF pages and stored in the site’s Study Binder. 
This study will be conducted in compliance with the regulations contained within CFR Part 11, 
electronic records/electronic signatures regulations. 
15.6. 
Retention of Study Records 
GCP regulations require that the investigator retain all documentation related to this clinical trial 
for a period of 2 years after the approval of the NDA in the U.S. (or Product License outside the 
U.S.) for this drug or 2 years after the withdrawal of the IND.  These records include the protocol 
and copies of all documents submitted to pSivida Corp., or to government authorities, subject 
records (including signed informed consent forms, subject charts, eCRFs, and other source 
documents), IRB/EC approvals and correspondence, records of drug accountability, and all study 
communications, whether written, telephonic, or electronic.  None of the required documents 
will be destroyed or transferred to the control of another party without the written approval of 
pSivida Corp. 
15.7. 
Monitoring of the Study 
Representatives or affiliates of pSivida Corp. will contact the investigator and his/her staff prior 
to the start of the trial to review the procedures to be followed in conducting the study and 
recording the findings, and to confirm the facility’s readiness to conduct the trial. 
Monitors may observe all aspects of subject treatment as frequently as necessary to ensure 
adherence to the protocol.  The investigator and his staff will cooperate with pSivida Corp. 
representatives and will provide any missing information and grant access to all study 
documentation. 
Representatives of pSivida Corp. may audit the study periodically to ensure that all records are 
correct and complete.   
15.8. 
Discontinuation of the Study 
pSivida Corp. reserves the right to discontinue this study for administrative reasons at any time. 
The trial may also be terminated prematurely if unexpected adverse events occur or if the 
investigator does not adhere to the protocol. 


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15.9. 
Policy for Publications 
The detailed procedures for the review of publications are set out in the clinical trial agreement 
entered into with pSivida Corp. in connection with this study. 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB/EC as appropriate.  The investigator must submit written 
approval from an IRB/EC to pSivida Corp. or the CRO before the investigator may initiate this 
study. 
The Principal Investigator is responsible for informing the IRB/EC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB/EC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by the 
IRB/EC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  pSivida Corp. or the CRO will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/EC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice and applicable 
regulatory requirements. 
16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study.  
Subjects must also be notified that they are free to discontinue from the study at any time.  The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures.  The subject must have a copy of the signed and dated ICF, which will be either a 
copy of the signed original or another signed original, in accordance with applicable local 
requirements. 
A signed original copy of the ICF must be retained by the study site. 


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17. 
LIST OF REFERENCES 
Alimera Biosciences. Integrated summaries of efficacy and safety. NDA201923 2011. 
Brunton LL, Lazo JS, Parker KL. Adrenocorticotropic Hormone: Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors 
of the Synthesis and Actions of Adrenocortical Hormones. In LL Brunton (Ed.) Goodman & Gilman’s The Pharmacological 
Basis of Therapeutics 2006 (pp. 1593-1600). 
Campochiaro P, Nguyen QD, Hafiz G, Bloom S, Brown DM, Busquets M, Ciulla T, Feiner L, Sabates N, Billman K, Kapik B, 
Green K, Kane FE. Aqueous levels of fluocinolone acetonide after administration of fluocinolone acetonide inserts or 
fluocinolone acetonide implants. Ophthalmology 2013; 120: 583-587. 
Casilli L, Sauro M, Biraschi LM, Tarantino P, Michelazzi L. Toxicological studies on halopredone acetate. Arzneimittel 
Forschung-Drug Research 1977; 27: 2102-2108. 
Hogan MJ, Kimura SJ, Thygeson P. Signs and symptoms of uveitis. I. Anterior uveitis. Am J Ophthalmol 1959; 47: 155–70. 
Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of 
uveitis nomenclature for reporting clinical data. Results of the First International Workshop, Am J Ophthalmol 2005; 140: 509-
16. 
Kihlstrom L, Lundberg C. Teratogenicity study of the new glucocorticoid budesonide in rabbits. Arznemittel Forschung-Drug 
Research 1987; 37: 43-46. 
Lan KKG, Wittes J. The β-value: a tool for monitoring data. Biometrics 1988; 44: 579-585. 
Maca SM, Amon M, Findl O, Kahraman G, Barisani-Asenbauer T. Efficacy and tolerability of preservative-free and preserved 
diclofenac and preserved ketorolac eyedrops after cataract surgery. Am J Ophthalmol. 2010; 149: 777-784. 
Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, Writing Committee: Kempen JH, Altaweel MM, Holbrook 
JT, Jabs DA, Louis TA, Sugar EA, Thorne JE. Randomized comparison of systemic anti-inflammatory therapy versus 
fluocinolone acetonide implant for intermediate, posterior and panuveitis: the multicenter uveitis steroid treatment trial. 
Ophthalmology 2011; 118: 1916–1926 
Nehmé A, Lobenhofer EK, Stamer WD, Edelman JL. Glucocorticoids with different chemical structures but similar 
glucocorticoid receptor potency regulate subsets of common and unique genes in human trabecular meshwork cells. BMC 
Medical Genomics 2009; 2: 58-71. 
Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory activity in intermediate and 
posterior uveitis. Ophthalmology 1985; 92: 467–71. 
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 35: 549-556. 
Pearson PA, Comstock TL, Ip M, Callanan D, Morse LS, Ashton P, Levy B, Mann ES, Eliot D. Fluocinolone acetonide 
intravitreal insert for diabetic macular edema: a 3-year multicenter, randomized controlled clinical trial. Ophthalmology 2011; 
118: 1580-1587. 
Retisert Prescribing Information (June 2011). 
Scoville B, Krieglstein GK, Then E, Yokoyama S, Yokoyama T. Measuring drug-induced eye irritation: a simple new clinical 
assay. J Clin Pharmacol 1985; 25: 210–218. 
Suttorp-Schulten MS, Rothova A. The possible impact of uveitis in blindness: a literature survey. Br J Ophthalmol 1996; 80: 844-
848. 


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18. 
APPENDIX I: MEASUREMENT OF BCVA BY ETDRS 
Introduction: 
The procedure for carrying out the testing of best-corrected distance visual acuity will be covered 
in this appendix.  Visual acuity is always tested with the subject’s best correction.  Visual acuity 
should be measured without the pupils being dilated and before slit lamp biomicroscopy 
examination or any drops or ointments are used. 
Equipment and Facilities: 
The best-corrected visual acuity (BCVA) of participants will be measured according to the 
standard procedure originally developed for Early Treatment Diabetic Retinopathy Study 
(ETDRS) and adapted for the AREDS protocol.  To ensure best-corrected visual acuity 
measurement, manifest refraction must be completed prior to visual acuity testing.  The study 
requires a set of three Lighthouse Distance Visual Acuity Test Charts (Lighthouse 2nd edition or 
Precision Vision “ETDRS”) and a retro illuminated box providing standardized chart 
illumination. For patients who are illiterate or not familiar with the English alphabet, BCVA will 
be determined using the Tumbling E ETDRS charts.  
The charts and the box are manufactured by:   Lighthouse Low Vision Products 
 
 
 
 
 
 
  36-02 Northern Boulevard 
 
 
 
 
 
 
  Long Island City, New York 11101 
 
 
 
 
 
 
  Telephone: (718) 937-6959 
 
 
 
 
 
 
 
Or 
 
 
 
 
 
 
  Precision Vision 
 
 
 
 
 
 
  745 North Harvard Ave. 
 
 
 
 
 
 
  Villa Park, IL 60181 
 
 
 
 
 
 
  Telephone: (630) 833-1454 
Visual acuity testing in this study is required at a distance of 4 meters and for participants with 
reduced vision, at 1 (one) meter.  The 4-meter distance should be clearly and permanently 
marked.  The 1-meter distance is to be measured with a 1-meter stick with the participant seated 
in a chair. 
Visual acuity charts: 
Chart R is used for refraction.  Chart 1 is used for testing visual acuity of the right eye.  Chart 2 
is used to test visual acuity of the left eye.  The features of the charts are 5 high-contrast Sloan 
letters in each of the 14 lines.  Lines are of equal difficulty, and follow a geometric progression 
of letter size from line to line.  Further, charts 1, 2 and R have different letter sequences to avoid 
memorization by the participants.  Participants should be prevented from seeing Chart 1 and 
Chart 2 until refraction has been completed, and the visual acuity testing is to begin. 
Retro-illumination box: 


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The dimensions of the light box are 24 ¾ inches by 25 ¾ inches by 7 inches.  The box can be 
mounted on a wall or on a 5-pronged wheel-based stand, manufactured by Lighthouse Low 
Vision Products.  Each prong is about 14 inches long, and 2 of the 5 wheels are lockable.  When 
the box is mounted on the stand, the height can be varied.  The charts are stored in the back of 
the light box. 
Room lights should be off during refraction and visual acuity testing.  The box itself provides 
sufficient illumination for the examiner to record the test results.  Additional light can have an 
adverse effect.  If absolutely necessary, a small desk type light may remain on; however, the 
light beam should be directed away from the light box and the subject.  The light box is equipped 
with two General Electric Cool Daylight 20-watt fluorescent tubes and ballast.  As the 
illumination of fluorescent tubes diminishes by 5% during the first 100 hours and by another 5% 
during the next 2,000 hours, the following should be done: 
• New tubes should be kept on for about four days (approx. 96 hours) to “warm-up”, time 
“on” does not have to be continuous. 
• All tubes should be replaced once a year. 
• It is advisable to periodically check the fluorescent tubes for proper function.  
Replacement tubes can be purchased at a local hardware store or Lighthouse Low Vision 
Product. 
Visual acuity lanes: 4 meter and 1 meter: 
A distance of exactly 4 meters (13 feet, 1 ½ inches, or 157 ½ inches) is required between the 
participant’s eye and the visual acuity chart for the 4-meter test.  A distance of exactly 1 meter 
(39 3/8 inches) is required for the 1-meter test. 
The room for visual acuity testing must have enough room for the 4-meter lane as well as the 
light box and the participant.  
Mounting the light box: 
The light box should be mounted at such a height that the top of the third row of letters (0.8 Log 
MAR) is 49 ± 2 inches from the floor. 
Wall mounting:  In addition to the 4-meter lane, 7 inches must be allowed for the depth of the 
box, plus space for the participant to sit or stand. 
Stand mounted box:  In addition to the 4-meter lane, 13 inches must be allowed for two of the 
stand’s casters to touch the rear wall or a line marked on the floor if there is no wall, plus space 
for the participant to sit or stand. 
Marking the distance: 4 meters 
If the chair and visual acuity box are permanently affixed, distance measurements need only to 
be made once.  If the box is mounted on the wall, but the participant’s chair is not permanently 
affixed, the 4-meter distance from the participant’s eye to the chart must be clearly and 
permanently marked. 
If the box is mounted on a movable stand, the 4-meter distance must be clearly and permanently 
marked on the floor.  The location of the box must also be clearly and permanently marked on 


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the floor and placement should be checked between participants.  When the stand touches the 
rear wall, two of the casters should touch the wall. 
Marking the distance: 1 meter 
The 1-meter distance is measured from the eye of the participant, with his or her back firmly 
against the back of the chair, to the second or fourth letter of the third line of the eye chart.  A 1-
meter measuring stick should be used. 
18.1. 
Refraction Technique 
All visual acuity will be measured with the participant’s best-corrected vision.  No pinhole 
testing will be done.  It is strongly advised that the refraction be done with the 4-meter distance.  
If for practical reasons, the 10-foot distance must be used, the same refraction procedure should 
be performed as for the 4-meter distance (visual acuity scores will be adjusted accordingly).  The 
right eye should be refracted first, then the left eye. 
If the participant wears contact lenses and has glasses, they should be reminded that they would 
be unable to wear their contact lenses for the duration of the study.  At the screening visit, if the 
subject is wearing contact lenses, they should be removed and refraction and visual acuity should 
not be done for at least half an hour for soft lenses and one hour for hard lenses. 
18.1.1. 
Approximate Refraction 
If results of a previous subjective refraction are available, they can be used as the beginning of 
approximate refraction.  Otherwise the following procedures should be used: 
• If the participant’s uncorrected visual acuity is 20/200 or better, and the participant does 
not have glasses for distance vision, the beginning approximate refraction is no lens 
correction (plano). 
• If the participant’s uncorrected visual acuity is less than 20/200 in either eye with their 
present distance glasses, or without correction if the subject does not have glasses, 
retinoscopy should be performed by an examiner proficient in this procedure.  An 
acceptable alternative is to conduct an arbitrary trial with any lens to bring visual acuity 
to 20/200 or better.  The lens corrections obtained are used as the beginning approximate 
refraction for determining best-corrected acuity. 
• If the participant’s visual acuity is 20/200 or better with participant’s current distance 
glasses, the glasses are measured with a lensometer, and these measurements are to be 
used as the beginning approximate refraction. 
18.1.2. 
Subjective Refraction 
The trial frame is placed and adjusted on the subject’s face so that the lens cells are parallel to 
the anterior plane of the orbits and centered in front of the pupil.  The left eye is occluded and the 
beginning approximate refraction, as previously determined, is placed in the right lens cells with 
the cylindrical correction anterior. 
• It is permissible to use a Phoropter for subjective refraction.  However, for testing visual 
acuity, the lenses from the last Phoropter refraction must be placed in trial frames and the 


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final sphere must be rechecked as described in “Refining Final Spherical Power” (Section 
18.1.5). 
• If the participant’s visual acuity is too poor to see the largest letters on the chart at the 4-
meter distance, refer to “Refraction for Participants with Poor Visual Acuity” (Section 
18.1.7). 
18.1.3. 
Determination of Spherical Refraction 
With the beginning refraction in place, the visual acuity of the right eye is assessed and noted.  A 
+0.50 sphere is then held in front of the right eye and the participants are asked if the vision is  
“better”, “worse”, or “no different”, while they are looking at the smallest line they can read 
well. 
• If vision is improved, or there is no change, the sphere in the trial frame is replaced with 
one that is one-half diopter more plus.  The +0.50 sphere is held in front of the study eye 
and participant is asked again if the vision is “better”, “worse”, or “no different.”  This 
process is repeated until the participant says that the additional +0.50 sphere make the 
vision worse.  The lens should be left in place for 10 to 15 seconds in an attempt to 
evaluate whether the participant is accommodating.  If the vision clears during this 
period, the +0.50 sphere may be added again.  Successive attempts to evaluate additional 
plus lenses should be made with the 10 to 15 second delay.  If there is no evidence of 
unrelaxed accommodation, the delay period is no longer necessary. 
• Whenever the participant says that the vision is worse and no longer improves, the +0.50 
sphere is removed from the front of the trial frame.  By this process, the highest plus 
sphere that is tolerated without blurring the participant’s vision has been determined. 
• Next, a –0.37 sphere is held in front of the trial frame and the participant is asked if 
vision is better, worse, or no different.  If vision is improved, the participant is requested 
to read the chart, and if at least one more letter is read on the smallest line noted 
previously or the next smaller line, the sphere in the trial is replaced by a sphere that is 
0.25 diopter less plus.  In certain situations, the participant is unable to read more letters, 
but is convinced that the vision is actually improved.  If the examiner believes that this is 
the case, the additional minus sphere lens can be added.  At any stage in the examination, 
no more than 0.25 diopters of minus sphere should be added without an increase in the 
number of letters read correctly.  The additional minus sphere lens should not be added if 
the participant reads fewer letters but states that visual acuity is better. 
• If the participant says the vision is “no different” or “worse”, no minus power should be 
added and the determination of the sphere correction is complete. 
18.1.4. 
Determination of Cylindrical Refraction 
• Cylinder Axis Determination 
 
If the beginning approximate refraction contains a cylinder correction, changes in 
cylindrical axis are tested by adding a 0.25, 0.37 or 0.50 diopter cross-cylinder axis, first 
with the positive axis at 45 degrees to one side of the cylinder axis and then with the 
positive axis 45 degrees to the opposite side of the cylinder axis.  Since neither position 


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may produce a clear image, the participant is encouraged to select the position producing 
less blur while focusing on a single round letter on the line above the lowest line on the 
chart they can read  when the cross cylinder is not held up before the trial frame.  If the 
participant cannot choose between the two positions of the cross-cylinder at the 
beginning of this test, the axis is moved 5 to 15 degrees, first in one direction and then in 
the other, with the cross-cylinder being checked in each position to confirm that the 
original axis was correct.  If the participant prefers one position of the cross-cylinder to 
the other and the cylinder in the trial frame is plus, the axis of the cylinder is moved 5 to 
15 degrees toward the positive axis of the cross-cylinder when it is in the position found 
to be less blurry by the participant. 
 
When the power of the cylinder is low or the participant’s discrimination is poor, larger 
shifts will produce more clear-cut answers.  The cross-cylinder is held again with the 
positive axis 45 degrees, first to one side, then to the opposite of the new cylinder axis, to 
determine which position produces less blur. 
• Cylinder Power Determination 
 
Change in cylinder power is tested by adding the cross-cylinder, first with the positive 
axis and then with the negative axis coincident with the cylinder axis.  The participant is 
requested to focus on a round letter on the lowest line of the chart they can read.  If the 
participant prefers the positive axis coincident with the cylinder axis, the power of the 
correcting plus cylinder is increased by a +0.25 diopter.  If the participant prefers the 
negative axis coincident with the cylinder axis, the total power of the correcting plus 
cylinder is reduced by 0.25 diopter.  This process is repeated until the participant finds 
neither position is better than the other.  As the plus cylinder is added, the examiner 
should notice that the spherical equivalent of the refraction is changed.  More minus 
sphere may be needed as the plus cylinder is added.  For every 0.50 diopter of cylinder 
power added, the sphere changes by –0.25 diopter.  If the beginning refraction is a pure 
sphere, the presence of an astigmatism is tested by arbitrarily placing a +0.25 cylinder at 
180 degrees in the trial frame, after having determined the highest-plus or least-minus 
sphere producing minimal blurring of vision, as described previously in Section 18.1.3.  
The refraction is continued by using the cross-cylinder to test for the axis and the cylinder 
power using the cross-cylinder technique outlined above. 
18.1.5. 
Refining Final Spherical Power 
When neither the power nor the axis of the cylinder can be improved, the power of the sphere is 
refined by testing with +0.25 sphere and –0.37 sphere and changing the spherical power as 
indicated previously in Section 18.1.3.  If the sphere is changed at this point, the cylinder should 
be rechecked.  
This process is repeated until no further significant lens changes are made. 


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18.1.6. 
Summary of Refraction Protocol 
At the end of the refraction, the sphere is checked and the participant neither tolerates increased 
plus nor improves with increased minus spheres.  Then the axis is checked and no change in this 
is indicated.  At this point, the refraction is considered complete. 
If, at the time of the refraction, the subject’s pupil is dilated it must be noted on the visual acuity 
worksheet. 
18.1.7. 
Refraction for Participants with Poor Visual Acuity 
If it is not possible to perform a subjective refraction at 10 feet or 4 meters because visual acuity 
is too poor for the participant to see the largest letters on the chart at this distance, the refraction 
should be attempted at 1 meter.  The procedure at 1 meter is the same as the procedure for 4 
meters.  However, the increments of lens power can be larger.  For the sphere, ± 1.00 diopter or 
more can be tested.  Cylindrical refraction can be assessed with the 0.5 or 1.00 than 0.25 diopter. 
If subjective refraction can be performed successfully at 1 meter, a +0.75 sphere should be 
subtracted from the 1-meter refraction to make the correction appropriate for the 4-meter 
distance. 
18.2. 
4-Meter Test and 1-Meter Test 
18.2.1. 
4-MeterTest: 
The distance from the participant’s eyes to the visual acuity chart must be exactly 4 meters (13 
feet and 1.5 inches). 
• The examiner should insure that the participant is sitting or standing comfortably, and 
that the head does not move back and forth during the test.  The participant’s eyes should 
always remain at the 4-meter distance. 
• The participant should be told the chart contains only letters and no numbers.  Should the 
participant forget these instructions and read a number, the examiner will remind the 
participant that the chart contains letters only and request a letter response in lieu of a 
number. 
• The examiner should ask the participant to read slowly. 
• The examiner should never point to the chart or to specific letters on the chart or read any 
letters during the test. 
• Each letter is scored as correct or wrong.  If the participant changes a response aloud 
before he or she has read the next letter aloud, that response is acceptable.  If the 
participant changes the response after the next letter has been read aloud, that next 
response is unacceptable. 
• Participants should be encouraged to guess.  The reasons are: a) it will help maximize 
their effort and help ensure uniformity among different clinical sites; b) it will help 
prevent bias if the participant has become unmasked. 
• The participant should be requested to give only one letter as a response. 


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• The participant can turn or shake his or her head if this improves visual acuity while the 
fellow eye remains securely covered. 
 
18.2.2. 
1-Meter Test: 
Eyes reading less than 20 letters correctly at 4 meters will be tested at 1 meter. 
• Before testing at one meter, a +0.75 sphere should be added to the 4-meter correction 
already in the trial frame to compensate for the closer distance. 
• The participant will be asked to read only the first six lines at 1 meter, making 30 the 
highest possible score at this distance. 
• After the test of the right eye with chart 1 is completed, repeat the test for the left eye 
with chart 2, starting at 4 meters.  When testing of the left eye is completed, chart 1 and 2 
should be removed from view and chart R mounted.  At this time refraction used for the 
right and left eyes should be introduced to the trial frame or the Phoropter and binocular 
visual acuity should be assessed using the same protocol as noted above. 
18.2.3. 
Scoring Best Corrected Visual Acuity: 
The examiner will record each letter correctly identified by circling the corresponding letter on 
the Visual Acuity Worksheet.  Letters read incorrectly or for which there was no guess will be 
marked with a slash mark through the corresponding letter. 
• Each letter read correctly is scored as one point. 
• The score of each line (which is zero if no letter was read) is recorded on the Visual 
Acuity Worksheet. 
• If testing at 1 meter is not required, 30 points are automatically added to the total number 
of letters read correctly. 
• If testing at 1 meter is done the score is determined by adding the total number of letters 
read at 4 meters to the total number read correctly at 1 meter. 
The total combined score (sum of the 4-meter and 1-meter test scores) is recorded on the Visual 
Acuity Worksheet.  Snellen-equivalent is calculated from the lowest line read with ≤ 2 letter 
errors (≥ 3 letters correct). 
18.2.4. 
Visual Acuity Grading Scale 
Measurement of best corrected visual acuity is measured with logarithmic visual acuity charts at 
a distance of 4 meters, and at 1 meter if visual acuity is worse than 20/100.  Participants are 
encouraged to make a maximum effort to read as many lines as possible. 


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19. 
APPENDIX 2: METHODS OF CLINICAL EVALUATION 
19.1. 
Ophthalmoscopy and Grading of Vitreous Haze  
Ophthalmoscopy will be performed to assess retinal and choroid appearances and vitreous haze 
(Nussenblatt 1985).  Indirect ophthalmoscopy will be performed for each eye with pupil dilation 
and should be completed after IOP measurement has been completed. 
Vitreous Haze Grading Scale 
The following scale will be used to define the extent of vitreous haze: 
Absent 
Clear view of optic disc, retinal vessels and nerve fiber layer 
Trace 
Slight blurring of optic disc margin and of normal striations and 
reflex of nerve fiber layer 
1+ 
Mild blurring of optic disc margin and slight loss of retinal vessel 
definition 
2+ 
Moderate blurring of optic disc margin and loss of retinal vessel 
definition 
3+ 
Optic nerve head and large vessels visible but borders quite (very) 
blurry 
4+ 
Optic nerve head obscured 
Figure 3: 
Vitreous Haze Scoring Convention 
The diagram on the 
right presents the 
scoring convention 
that will be used to 
identify a minimum 
of “> 2 step increase” 
of vitreous haze for 
the primary efficacy 
endpoint. 
 
 
 


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Anterior Chamber Cells Grading Scale  
Anterior chamber cells will be measured using a Haag/Streit or similar slit lamp at high 
magnification (1.6 X) 1-mm beam.  The same instrument, and when possible the same examiner 
should be used on each patient throughout the study.  Assessment will be made using the 
following scale (Jabs 2005). 
 
Field size: 1 mm by 1 mm slit beam 
0 
<1 cells/hpf 
0.5+ 
1-5 cells/hpf 
1+ 
6-15 cells/hpf 
2+ 
16-25 cells/hpf 
3+ 
26-50 cells/hpf 
4+ 
>50 cells/hpf 
Figure 4: 
Anterior Chamber Cell Scoring Convention 
The diagram on the 
right presents the 
scoring convention 
that will be used to 
identify a minimum 
of “> 2 step increase” 
of anterior chamber 
cells for the primary 
efficacy endpoint. 
 
 


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Fundus Examination 
The fundus assessments should be conducted using indirect ophthalmoscopy with a 20 diopter, 
28 diopter, or 30 diopter condensing lens.  In order to minimize variability, every effort should 
be made to have a single examiner conduct all assessments on a given subject. 
19.2. 
Intraocular Pressure  
Intraocular pressure will be assessed by applanation tonometry (preferably, Goldmann) and 
should be measured only after slit lamp examination has been completed.  The mean of 3 
measurements per eye will be recorded as the IOP.  All reasonable efforts should be made to 
have the same examiner obtain all IOP measurement for a given subject.  Measurement should 
be performed before dilated ophthalmoscopy. 
19.3. 
Humphrey Visual Field Measurement 
The 24-2 program will be used.  Measurement should be performed before ophthalmoscopy. 
 
20. 
APPENDIX 3: SUBJECTIVE OCULAR TOLERABILITY AND 
DISCOMFORT ASSESSMENT 
Subjects will be asked to grade ocular tolerability and discomfort in both eyes at all study visits. 
Subjective ocular discomfort grading 
Subjects will assess discomfort using the following subjective scale (Maca 2010).  This 
parameter will consist of questioning about superficial pain, foreign body, or gritty sensation, 
itching, burning, and other forms of non-specific discomfort. 
Grade 0: Absent 
Grade 0.5: Very mild 
Grade 1: Mild 
Grade 2: Moderate 
Grade 3: Severe 
Grade 4: Intolerable 
 
Subjective tolerability using visual analog scale for pain 
Subjects will assess tolerability using the following subjective scale (Scoville 1985).  A visual 
analogue scale is performed by asking subjects to indicate on an unmarked 100 mm line the 
intensity of their pain.  A mark of '0' represents no sensation while '100' indicates the worst 
imaginable pain.  The location of the mark on the line then is measured with a mm ruler to 
provide a numeric score. 


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SAP_001.pdf: 
 
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Confidential 
 
 
 
 
 
 
 
 
 
pSivida Corp. 
 
PSV-FAI-001 
 
A Phase III, Multi-national, Multi-center, Randomized, Masked, Controlled, 
Safety and Efficacy Study of a Fluocinolone Acetonide Intravitreal (FAI) 
Insert in Subjects With a Chronic Non-infectious Uveitis Affecting the 
Posterior Segment of the Eye  
 
05 January 2017 
Final Statistical Analysis Plan 
For US 
 
Version 4.1 
 
Prepared by: 
 
PPD 
3900 Paramount Parkway 
Morrisville, NC 27560 
 
 
 


pSivida Corp. 
 
                       Final Statistical Analysis Plan, Version 4.1 
PSV-FAI-001 
 
Date Issued: 05JAN2017 
 
  
 
 
 
II
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... IV 
1. 
INTRODUCTION ............................................................................................................ 1 
2. 
OBJECTIVES ................................................................................................................... 2 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 2 
3.1. 
OVERALL STUDY DESIGN AND PLAN .............................................................................. 2 
3.2. 
STUDY ENDPOINTS .......................................................................................................... 2 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 3 
4.1. 
SAMPLE SIZE ................................................................................................................... 5 
4.2. 
RANDOMIZATION, STRATIFICATION, AND MASKING ....................................................... 5 
4.2.1. 
MASKING OF STUDY TEAM ............................................................................................. 6 
4.3. 
ANALYSIS POPULATION .................................................................................................. 6 
4.3.1. 
Intent-to-Treat (ITT) ................................................................................................... 6 
4.3.2. 
Per Protocol (PP) ....................................................................................................... 6 
4.3.3. 
Safety ........................................................................................................................... 7 
5. 
SUBJECT DISPOSITION ............................................................................................... 7 
5.1. 
DISPOSITION .................................................................................................................... 7 
5.2. 
PROTOCOL DEVIATIONS .................................................................................................. 7 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................... 8 
6.1. 
DEMOGRAPHICS .............................................................................................................. 8 
6.2. 
BASELINE DISEASE AND OCULAR CHARACTERISTICS ..................................................... 8 
6.3. 
MEDICAL HISTORY .......................................................................................................... 9 
6.3.1. 
Non-ocular Medical History ....................................................................................... 9 
6.3.2. 
Ocular Medical History .............................................................................................. 9 
6.4. 
INCLUSION AND EXCLUSION CRITERIA ............................................................................ 9 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 10 
7.1. 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................... 10 
7.1.1 
Prior Medications ..................................................................................................... 10 
7.1.2 
Concomitant Medications ......................................................................................... 10 
7.1.2.1 
IOP Lowering Medication .................................................................................. 10 
7.1.3 
Systemic/Topical Treatment at Study Entry .............................................................. 11 
7.2. 
OCULAR SURGERIES ...................................................................................................... 11 
7.2.1 
Surgical Intervention to Control Elevated IOP ........................................................ 11 
7.2.2 
Cataract Surgeries .................................................................................................... 12 
7.3. 
STUDY TREATMENTS ..................................................................................................... 12 
7.3.1. 
Extent of Exposure .................................................................................................... 12 
8. 
EFFICACY ANALYSIS................................................................................................. 13 
8.1. 
PRIMARY EFFICACY ENDPOINT ..................................................................................... 13 
8.1.1. 
PRIMARY ANALYSIS ...................................................................................................... 14 


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8.1.2. 
Data Imputation ........................................................................................................ 15 
8.1.3. 
Sensitivity Analyses ................................................................................................... 15 
8.1.4. 
Subgroup Analyses .................................................................................................... 16 
8.2. 
EXPLORATORY EFFICACY ENDPOINTS ........................................................................... 17 
9. 
SAFETY ANALYSIS ..................................................................................................... 19 
9.1. 
ADVERSE EVENTS ......................................................................................................... 19 
9.1.1. 
Incidence of Adverse Events ..................................................................................... 20 
9.1.2. 
Relationship of Adverse Events to Study Treatment ................................................. 20 
9.1.3. 
Severity of Adverse Event.......................................................................................... 21 
9.1.4. 
Serious Adverse Events ............................................................................................. 21 
9.1.5. 
Adverse Events Leading to FAI Insert Removal ....................................................... 22 
9.1.6. 
Adverse Events Leading to Study Discontinuation ................................................... 22 
9.1.7. 
Death ......................................................................................................................... 22 
9.1.8. 
Adverse Events of Special Interest ............................................................................ 22 
9.2. 
OPHTHALMIC EXAMINATION ......................................................................................... 22 
9.2.1. 
Best-corrected Visual Acuity (BCVA) ....................................................................... 23 
9.2.2. 
Intraocular Pressure (IOP) ....................................................................................... 23 
9.2.3. 
Dilated Indirect Ophthalmoscopy ............................................................................. 24 
9.2.4. 
Slit Lamp Examination .............................................................................................. 24 
9.2.5. 
Vitreous Haze and Anterior Chamber Cells ............................................................. 24 
9.3. 
HUMPHREY 24-2 VISUAL FIELD TEST ........................................................................... 25 
9.4. 
OPTICAL COHERENCE TOMOGRAPHY (OCT) ................................................................ 25 
9.5. 
SUBJECTIVE OCULAR TOLERABILITY AND DISCOMFORT ASSESSMENT ......................... 26 
9.6. 
CLINICAL LABORATORY EVALUATIONS ........................................................................ 26 
9.7. 
VITAL SIGN MEASUREMENTS ........................................................................................ 27 
9.8. 
PHYSICAL EXAMINATION .............................................................................................. 27 
10. 
INTERIM ANALYSIS ................................................................................................... 27 
11. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 27 
12. 
REFERENCES ................................................................................................................ 27 
13. 
APPENDICES ................................................................................................................. 28 
13.1. 
SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS ............................................... 29 
13.2 
SAS CODE FOR MULTIPLE IMPUTATION METHOD......................................................... 31 
13.3 
NOTE FOR FDA REVIEWERS .......................................................................................... 33 


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IV
List of Abbreviations 
 
AE 
Adverse Event 
BCVA 
Best Corrected Visual Acuity 
CSFT 
Central Subfield Thickness 
eCRF 
Electronic Case Report Form 
EMEA 
United Kingdom, Germany, Hungary and Israel 
ETDRS 
Early Treatment Diabetic Retinopathy Study  
FA 
Fluocinolone Acetonide 
FAI Insert 
Fluocinolone Acetonide Intravitreal Insert 
FDA 
Food and Drug Administration 
IOP 
Intraocular Pressure 
ITT 
Intent to Treat 
IVRS 
Interactive Voice Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
OCT 
Optical Coherence Tomography 
PP 
Per-Protocol 
PT 
Preferred Term 
ROW 
Rest of World 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-Emergent Adverse Event 
US 
United States of America 
WHO 
World Health Organization 
VA 
Visual Acuity 
 
 
 


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1. Introduction 
pSivida Corp. is developing a drug product candidate to treat chronic non-infectious uveitis 
affecting the posterior segment of the eye. This includes posterior uveitis, intermediate uveitis, 
with or without anterior uveitis; and panuveitis. pSivida’s product candidate is an intravitreal 
insert that contains 0.18 mg of fluocinolone acetonide (FA) and releases FA into the vitreous 
humor for 36 months. 
 
Uveitis is defined as inflammation of the uveal tract (iris, ciliary body, choroids) or adjacent 
structures. The cause of inflammatory reaction of the inner eye can be infectious, traumatic, 
neoplastic or autoimmune. According to the classification scheme recommended by the 
International Uveitis Study Group, the disease can be classified on the basis of anatomic 
locations: anterior, intermediate, posterior, or panuveitis.  
 
Generally, posterior uveitis occurs in all age groups and affects people of different ethnic origins.  
The inflammation that affects the choroid and retina may be a primary intra-ocular process or 
may be an ocular manifestation of systemic disease. Posterior uveitis accounts for most of the 
loss of vision in eyes with uveitis, due to any one or more of the following: cystoid macular 
edema, choroidal neovascularization, glaucoma, retinal detachment, subretinal fibrosis, cataract, 
or optic disk atrophy. 
 
Uveitis is often a chronic disease requiring long-term medical therapy. Currently, medical 
management of chronic non-infectious uveitis affecting the posterior segment generally includes 
local administration of corticosteroid (topical, intra- or peri-ocular, and intravitreal) and/or 
systemic administration of steroids or immunosuppressants. The goal of therapy is to suppress 
the inflammation in the back of the eye. 
 
There are disadvantages associated with each of these therapies and their route of administration.  
All corticosteroid therapy, including systemic, is associated with ocular side effects, including 
cataract and elevated intraocular pressure (IOP); these side effects are more commonly observed 
with local therapy. Topical corticosteroid delivery is not effective in the treatment of 
intermediate or posterior uveitis due to its limited intraocular penetration. Peri-ocular 
corticosteroid injections may be required frequently and have the additional potential risk for 
globe perforation, orbital fibrosis, endophthalmitis and ptosis.  
 
A product that is relatively simple to administer and delivers corticosteroid locally for an 
extended period of time may offer significant benefits over existing local and systemic steroid 
therapies. 
 
The FAI insert to be used in the present study is virtually identical to Iluvien®, an intravitreal 
fluocinolone acetonide product candidate that has been inserted into the eyes of over  
800 subjects with diabetic macular edema, retinal vein occlusion, wet age-related macular 
degeneration or dry age-related macular degeneration. 
 


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Additionally, Retisert, a larger FDA-approved intraocular product that requires surgical 
implantation, also contains the same active ingredient as the FAI insert.  Compared to the FAI 
insert, Retisert delivers approximately 3 times as much FA at rates approximately 3 times faster.  
Retisert has been approved by FDA for the treatment of chronic non-infectious uveitis affecting 
the posterior segment of the eye [Retisert prescribing information (June 2001)]. 
 
pSivida Corp. is developing the FAI insert to provide local steroid therapy with an improved 
benefit/risk profile for patients with chronic non-infectious uveitis affecting the posterior 
segment of the eye.   
 
This US-specific statistical analysis plan (SAP) uses a revised definition of the primary efficacy 
endpoint that aligns with FDA guidance. Detailed rationale is provided in Appendix 13.3.   
2. Objectives 
The primary objectives of this study are to evaluate the safety and efficacy of a FAI insert in the 
management of subjects with chronic non-infectious uveitis affecting the posterior segment of 
the eye.  
3. Investigational Plan 
3.1. 
Overall Study Design and Plan 
This trial is a 36-month, Phase 3, multi-national, multi-center, randomized, masked, controlled, 
safety and efficacy study of FAI inserts in subjects with chronic non-infectious uveitis affecting 
the posterior segment of the eye. Clinical sites in the US, EMEA (United Kingdom, Germany, 
Hungary and Israel), and India will participate in this study. A total enrollment of approximately 
120 subjects is planned for this study. On Day 1, subjects will be randomized in a 2:1 ratio to 
either FAI insert or Sham injection. Subjects will be assessed according to the schedule of 
procedures and assessments (Appendix 15.1).   
 
Analyses of study data will be performed at the following three time points during the study: 
1. After all subjects have completed the Month 6 visit (or have been discontinued from the 
study prior to this visit).  The primary analysis of efficacy will occur at the Month 6 time 
point. 
2. After all subjects have completed the Month 12 visit (or have been discontinued from the 
study prior to this visit).   
3. After all subjects have completed the Month 36 visit (or have been discontinued from the 
study prior to this visit). 
Details on masked and unmasked personnel at the two time points are provided in Section 4.2.1.  
3.2. 
Study Endpoints 
The primary efficacy endpoint is the proportion of subjects who have a recurrence of uveitis in 
the study eye within 6 months after receiving study treatment. Recurrence is captured on the 
Recurrence of Uveitis eCRF page and, for the US/FDA, is defined as: 
 


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 An increase in the vitreous haze of ≥ 2 steps, compared to baseline or any visit time point 
prior to Month 6 
OR 
 A deterioration in visual acuity of at least 15 letters BCVA, compared to baseline or any 
visit time point prior to Month 6 
Any criterion used to define recurrence must be attributable only to noninfectious uveitis. To 
prevent post-procedural inflammatory reactions from being reported as uveitis recurrences, 
assessments for recurrence of uveitis begin after the study Day 7 visit.  
 
The exploratory efficacy endpoints include: 
 Proportion of subjects who have a recurrence of uveitis in the study eye within 12 months 
and 36 months 
 Proportion of subjects who have a recurrence of uveitis in the fellow eye (within 
6 months, 12 months and 36 months) 
 Mean change from baseline in best-corrected visual acuity (BCVA) letter score in the 
study eye (at 6 months, 12 months and 36 months) 
 Number of recurrences of uveitis (within 6 months, 12 months and 36 months) 
 Time to recurrence of uveitis in the study eye (within 6 months, 12 months and 
36 months) 
 Number of adjunctive treatments required to treat recurrences of uveitis (within  
6 months, 12 months and 36 months) 
 Resolution of macular edema, as measure by OCT imaging (at 6 months, 12 months and 
36 months) 
 
In addition, the following safety endpoints will be included in the analysis: 
 Systemic adverse events 
 Ocular adverse events, including intra-ocular pressure (IOP) elevation 
 Medications/procedures required to control elevated IOP 
 Development or worsening of cataract 
 Cataract-related procedures 
 Clinically significant ocular changes 
 Treatment related adverse events  
4. General Statistical Considerations 
Continuous data will be described using descriptive statistics (i.e. n, mean, standard deviation, 
median, minimum, and maximum). Categorical data will be described using the subject count 
and percentage in each category. For the summary statistics of all numerical variables unless 
otherwise specified, minimum and maximum will be displayed to the same level of precision as 
reported. Mean and median will be displayed to one level of precision greater than the data 
collected. Standard deviation / standard error will be displayed to two levels of precision greater 
than the data collected. P-values will be rounded to three decimal places. If a p-value is less than 
0.001 it will be reported as “<0.001.” If a p-value is greater than 0.999 it will be reported as 
“>0.999.” Data will be displayed in all listings sorted by treatment group.  
 


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Subjects will be identified in the listings by the subject identification number concatenated with 
the investigator number. 
 
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the non-zero counts. A row denoted “Missing” will be included in count 
tabulations where specified on the shells to account for dropouts and missing values. The 
denominator for all percentages will be the number of subjects in that treatment within the 
analysis population of interest, unless otherwise specified. 
 
Unless otherwise specified, baseline will be defined as the last non-missing evaluation prior to or 
on the date of treatment injection (Day 1). The study day will be calculated as assessment date – 
date of treatment injection (Day 1) + 1. 
 
For all efficacy and safety analyses, analysis visit windows will be used for assigning 
assessments to an analysis visit, as follows: 
 
Scheduled Visit 
Target Day 
Visit Window (Days) 
Screening 
-30 to -1 
Not applicable 
Day 1 
1 
Not applicable 
Day 7 
7 
5 to 9 
Day 28 
28 
25 to 31 
Month 2 
60 
53 to 67 
Month 3 
90 
83 to 97 
Month 6 
180 
152 to 208 
Month 9 
270 
242 to 298 
Month 12 
360 
332 to 388 
Month 18 
540 
512 to 568 
Month 24 
720 
692 to 748 
Month 30 
900 
872 to 928 
Month 36 
1080 
1052 to 1108 
Only those assessments which are assigned to an analysis visit will be included in the summary 
tables and figures which are presented by visit. For summaries of an event at or before a given 
time point, such as recurrence at Month 12, all assessments (including unscheduled visits) on or 
before the upper limit of the corresponding visit window will be considered. All assessments will 
be presented in the data listings.  
 
For summaries presented by 3 month time intervals through Month 12, the intervals will be 
defined based on study days and the analysis visit windows, as follows: 
 Day 1 to 3 months: day 1 to day 97 (upper limit of Month 3 visit window) 
 3 to 6 months: day 98 to day 208 (upper limit of Month 6 visit window) 
 6 to 9 months: day 209 to day 298 (upper limit of Month 9 visit window) 
 9 to 12 months: day 299 to day 388 (upper limit of Month 12 visit window) 
 
For summaries presented by 6 month time intervals, the intervals will be defined based on study 
days and the analysis visit windows, as follows: 
 Day 1 to 6 months: day 1 to day 208 (upper limit of Month 6 visit window) 
 6 to 12 months: day 209 to day 388 (upper limit of Month 12 visit window) 


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 12 to 18 months: day 389 to day 568 (upper limit of Month 18 visit window) 
 18 to 24 months: day 569 to day 748 (upper limit of Month 24 visit window) 
 24 to 30 months: day 749 to day 928 (upper limit of Month 30 visit window) 
 30 to 36 months: day 929 to day 1108 (upper limit of Month 36 visit window) 
 
The Month 6 analysis will include all assessments (events, medications, etc.) with a start day on 
or before the upper limit of the Month 6 visit window (study day 208). The Month 12 analysis 
will include all assessments (events, medications, etc.) with a start day on or before the upper 
limit of the Month 12 visit window (study day 388). The analysis at Month 36 will include all 
data in the database.  
 
For tabulations of data on the Safety population, subjects who were randomized but did not 
receive treatment will not be included; however data for all subjects in the Safety population will 
be included in the data listings.  In the listings, subjects who did not receive treatment will be 
grouped separately by their randomized treatment assignment (i.e., FAI Insert - Not Treated, 
Sham Injection - Not Treated). Percentages for Safety population summaries will be based on the 
total number of subjects who receive treatment. 
 
All analyses will be conducted using SAS Version 9.2 or higher. 
4.1. 
Sample Size 
A two group continuity corrected Chi-square test with a 0.05 two-sided significance level will 
have 89% power to detect the difference between a Sham group recurrence free rate of 0.600 and 
a FAI treated group recurrence free rate of 0.880 (odds ratio of 0.205) when the sample sizes are 
40 and 80, respectively (a total sample size of 120).  
4.2. 
Randomization, Stratification, and Masking 
Subjects will be randomly assigned in a 2:1 ratio to either the FAI insert or sham injection 
through a central Interactive Voice Response System (IVRS). A blocked randomization will be 
used and randomization will be stratified on the basis of systemic treatment to control uveitis at 
the time of study entry. The three strata are: Not receiving systemic treatment, Receiving 
systemic treatment – corticosteroid therapy, and Receiving systemic treatment – 
immunosuppressive therapy. Stratification will be achieved dynamically through the IVRS.   
 
To minimize bias, two investigators will be used at each study site. The unmasked treating 
investigator will inject the FAI insert or perform a sham injection and perform all assessments on 
study Day 1. The second investigator will serve as the masked assessing investigator and will 
perform all study assessments after Day 1. Only the unmasked treating investigator will know 
the assigned study treatment. Study personnel will use every reasonable effort to maintain the 
study mask.   
 
Unmasking a subject’s treatment to the assessing investigator should only be done in emergency 
situations for reasons of subject safety. In the event that an emergency unmasking is required, the 
assessing investigator/medically qualified designee has the authority to unmask a subject’s 
treatment using IVRS, or its backup system if IVRS is not functioning. If possible, the assessing 
investigator/medically qualified designee should contact the PPD medical monitor or designee 


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before breaking the mask. When the masked treatment code is broken, the date and time of 
unmasking, name of person doing the unmasking, and the reason for unmasking must be fully 
documented in the source documentation. Treatment unmasking will also be recorded on the 
eCRF, including whether the FAI insert was removed and if so, the removal date. In the rare 
event that the FAI insert is removed, the subject should continue to be followed for safety and 
recurrence of uveitis through Month 36.    
 
Randomization and unmasking data, for those subjects who were unmasked during the study, 
will be presented in a listing.  
4.2.1. Masking of Study Team 
Prior to the Month 6 database lock, study team members at PPD and pSivida Corp. will be 
masked to the treatment assignments, with the exception of the PPD randomization team. After 
the Month 6 database lock, the PPD Biostatistics, Programming and Medical Writing team 
members and pSivida will become unmasked. The PPD Clinical and Data Management team 
members will remain masked to subject-level treatment assignments until after the Month 36 
database lock.   
4.3. 
Analysis Population 
4.3.1. Intent-to-Treat (ITT) 
The ITT population will include all randomized subjects. The ITT population will be used for the 
primary efficacy analysis and all efficacy endpoints. 
All subjects in the ITT population will be analyzed according to the treatment they were 
randomized to receive and not according to what they actually received, in the event there is a 
discrepancy.  Similarly, in any ITT analysis by systemic treatment at study entry (randomization 
stratification factor), subjects will be analyzed by the strata to which they were randomized, not 
the actual strata, in the event there is a discrepancy.  
4.3.2. Per Protocol (PP) 
Analysis on the PP population will be used as a supplement to the ITT analysis and will be 
performed for all efficacy endpoints. The PP population will be defined separately for the  
Month 6, Month 12 and Month 36 analyses and will exclude all subjects in the ITT population 
who meet any of the following criteria: 
 Received systemic treatment for recurrence of uveitis in fellow eye 
 Received an imputed endpoint at the 6 month (or the 12 month or the 36 month) endpoint 
of the study 
 Failed screening, without exemption, but received FAI insert 
 Had a major protocol deviation   
Protocol deviations, both major and minor, will be identified prior to database lock and study 
unmasking at Month 6 and prior to database locks at Months 12 and 36. The review and 
identification of protocol deviations at Months 12 and 36 will be conducted in an unmasked 
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All subjects who failed screening but received FAI insert will be determined at Month 6 database 
lock.  
 
Additional sensitivity analyses involving alternative definitions of the PP population may be 
conducted, if warranted.  
 
All subjects in the PP population will be analyzed according to the treatment actually received 
and not according to the treatment they were randomized to receive, in the event there is a 
discrepancy.  Similarly, in any PP analysis by systemic treatment at study entry (randomization 
stratification factor), subjects will be analyzed by the actual strata to which they belong and not 
according to the strata under which they were randomized, in the event there is a discrepancy. 
 
4.3.3. Safety 
The Safety population will include all randomized subjects. All subjects in the Safety population 
will be analyzed according to the treatment actually received and not according to the treatment 
they were randomized to receive, in the event there is a discrepancy.  Similarly, in any Safety 
analysis by systemic treatment at study entry (randomization stratification factor), subjects will 
be analyzed by the actual strata to which they belong and not according to the strata under which 
they were randomized, in the event there is a discrepancy. 
5. Subject Disposition 
5.1. 
Disposition 
Subject disposition will be summarized for the ITT population. A disposition of subjects includes 
the number and percentage of subjects for the following categories: subjects randomized, 
subjects who completed the study, subjects who discontinued from the study, subjects in the 
Safety population, subjects in the ITT population, and subjects in the Month 6, Month 12 and 
Month 36 PP populations. All percentages will be based on the number of subjects randomized. 
 
The reasons for study discontinuation will also be summarized in the disposition table. The 
reason for study discontinuation includes the following: adverse event, lack of efficacy, lost to 
follow-up, death, subject voluntarily withdrew, physician decision, sponsor decision, and study 
cancelled. 
 
Subject disposition data will be presented in a listing. 
5.2. 
Protocol Deviations 
The investigator is not to deviate from the requirements from this protocol without prior approval 
from pSivida Corp. unless necessitated by a medical emergency (i.e., those that impact subject safety 
or the validity of the study).  Any deviation from the protocol, with or without prior pSivida 
approval, will be recorded including the following information: 
 
Investigator site 
 
Subject 
 
Subject visit 
 
Description (including associated Significant Protocol Deviation rule number, if applicable) 


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 
Date of occurrence 
 
Ethics Committee notification date if known 
 
Significant (Yes/No) 
 
Significant protocol deviations will be defined in the Significant Protocol Deviations Rules 
document.  Each significant deviation will be assigned a rule number. As the study is ongoing, 
additional significant protocol deviations can also be spontaneously identified or defined during 
trending and review of protocol deviations by pSivida and/or the project team during the 
regularly planned study deviation review meetings and the significant Protocol Deviations Rules 
document will be updated.  
 
All protocol deviations will be reviewed and assessed as to significance prior to each database 
lock. The list of protocol deviations (significant or minor) that are additionally considered major 
for the purposes of analysis (i.e. result in exclusion from the PP population) will also be 
identified prior to each database lock.   
6. Demographics and Baseline Characteristics 
6.1. 
Demographics 
A summary of demographics and baseline information will be presented for the ITT and Safety 
populations. Summaries will be generated for the Safety population only if there are randomized 
subjects who do not receive treatment. The demographic characteristics consist of age (years), 
sex, race, ethnicity, and iris color. The baseline characteristics consist of baseline height (cm), 
baseline weight (kg), and baseline body mass index (BMI) (kg/m^2). Body mass index is 
calculated as (body weight in kilograms) / (height in meters)2. 
 
A subject’s age in years is calculated using the date of the informed consent and date of birth. 
Age (years), baseline height (cm), baseline weight (kg), and baseline BMI (kg/m^2) will be 
summarized using descriptive statistics. The number and percentage of subjects by age category 
(<=20, 20 - < 40, 40 - < 60, >= 60), sex (Male, Female), race (White, Black, Asian, American 
Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and Other) and ethnicity 
(Hispanic or Latino, Not Hispanic or Latino), and iris color (Black, Brown, Hazel, Green, Blue, 
Grey, and Other) will also be reported. Percentages will be based on the total number of subjects 
in the ITT or Safety population, as applicable.     
 
Subject demographic and baseline characteristics will be presented in a listing. 
6.2. 
Baseline Disease and Ocular Characteristics 
A summary of baseline disease characteristics will be presented for the study eye and fellow eye 
for the ITT and Safety populations. Summaries will be generated for the Safety population only 
if there are randomized subjects who do not receive treatment. The baseline characteristics 
consist of study eye, randomization strata for systemic treatment to control uveitis, duration of 
uveitis (years), number of recurrences in the last 12 months, lens status, presence of cataract, 
history of vitrectomy procedure and history of incisional surgery to control elevated IOP.  
 


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Duration of uveitis is calculated as (Screening date – date of onset of uveitis +1)/ 365.25 and will 
be summarized using descriptive statistics. For partial onset dates, a missing month will be 
imputed as January and a missing day will be imputed as the first of the month.  
 
The number and percentage of subjects by study eye (OD, OS), randomization strata (Not 
receiving systemic treatment, Receiving systemic treatment – corticosteroid therapy, Receiving 
systemic treatment – immunosuppressive therapy), duration of uveitis (< 2 years, 2 to 5 years, > 
5 years), number or recurrences (<= 2, >2), lens status (phakic, aphakic, and pseudophakic), 
presence of cataract for subjects with a lens status of phakic, history of vitrectomy procedure, 
and history of incisional surgery to control elevated IOP will also be reported.  Percentages will 
be based on the total number of subjects in the ITT or Safety population, as applicable.   
 
In addition, baseline ocular characteristics will be summarized for the study eye. The baseline 
ocular characteristics consist of severity of macular edema, IOP (mmHg), and BCVA (letters). 
Baseline IOP and BCVA will be summarized using descriptive statistics. The number and 
percentage of subjects by baseline severity of macular edema (CSFT < 300 microns, CSFT >= 
300 microns) will also be reported. 
 
Subject baseline disease and ocular characteristics will be presented in a listing.  
6.3. 
Medical History 
6.3.1. Non-ocular Medical History 
The number and percentage of subjects with any non-ocular medical history and current non-
ocular conditions will be summarized overall and for each body system for the ITT population. 
Body systems will be included as recorded on the eCRF. Percentages will be calculated based on 
number of subjects in the ITT population.  
 
Subject non-ocular medical history data, including specific details on the condition/diagnosis and 
start/end dates, will be presented in a listing. 
6.3.2. Ocular Medical History  
Any clinically significant ocular conditions within the 12 months prior to Screening will be 
recorded on the eCRF. Subject ocular medical history data, including specific details on the 
condition/diagnosis, location (OS, OD, and OU), study eye designation, treatment required, and 
start/end dates, will be presented in a listing. 
6.4. 
Inclusion and Exclusion Criteria 
Prior to randomization, the investigator will assess whether the subject fulfills all of the inclusion 
and exclusion criteria outlined in the protocol. If a subject does not fulfill all of the requirements, 
the specific inclusion criterion not met or exclusion criterion which was met will be recorded on 
the eCRF. This information and whether the sponsor granted a waiver will be presented in a 
listing.  


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7. Treatments and Medications 
7.1. 
Prior and Concomitant Medications 
Medications and systemic/topical treatments for uveitis at study entry will be coded using the 
WHO Drug Dictionary (WHO201209 version or higher).  
 
All summaries will be provided for ocular medications and non-ocular medications, separately. 
Ocular medications will be presented by eye (study, fellow).  
 
All medication and systemic/topical treatment data will be presented in listings.  
7.1.1 Prior Medications 
Prior medications are defined as those medications with a recorded end date prior to the initiation 
of study treatment. The total number of prior medications and the number and percentages of 
subjects with at least one prior medication will be summarized by treatment group. The number 
and percentages of all prior medications will be summarized by treatment group and preferred 
term. All summaries will be performed using the Safety population. 
7.1.2 Concomitant Medications 
Concomitant medications are defined as those medications which are taken on or after the 
initiation of study treatment (Day 1). This includes medications which start prior to Day 1 but 
continue while the subject is on treatment.  
 
The total number of concomitant medications and the number and percentages of subjects with at 
least one concomitant medication will be summarized by treatment group. The number and 
percentages of all concomitant medications will be summarized by treatment group and by ATC 
level 1 term, ATC level 2 term, and preferred term. An additional summary of the number and 
percentage of subjects with at least one concomitant medication for each of the specified reasons 
for medication (recurrence of uveitis, treatment emergent AE, increased IOP, cataract, other) will 
be summarized by treatment group and by ATC level 1 term, ATC level 2 term, and preferred 
term. All summaries will be performed using the Safety population. 
7.1.2.1  IOP Lowering Medication 
The number and percentage of subjects requiring IOP lowering medication to control elevated 
IOP will be summarized by treatment group, eye (study, fellow), and time interval. Any systemic 
medications will be summarized as received in both the study and fellow eyes. IOP lowering 
medications will be identified as those medications with a reason for medication of “Increased 
IOP”. Incidence will be summarized overall (through 6, 12 or 36 months) and for 3 month time 
intervals through 6 or 12 months and 6 month time intervals from 12 to 36 months.   
 
The number of medications (one, two, ≥ three) required to achieve adequate IOP control will 
also be included in the summary. A single medication must be used for a minimum of 7 days. 
Multiple medications must be used concurrently for a minimum of 14 days.   
 
A summary of IOP lowering medications will also be presented by geographic region (United 
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Incisional Surgery, No History of Incisional Surgery). All summaries will be performed using 
the Safety population. 
7.1.3 Systemic/Topical Treatment at Study Entry 
If a subject is receiving systemic corticosteroids or immunosuppressants, or topical steroids to 
control uveitis prior to study enrollment, that subject will have such treatment ended within three 
months following study Day 1, in a manner that follows the standard of care for ending the 
specific treatment.  For example, some systemic treatment regimens may be ended immediately, 
while others require a period of gradual dose reduction (tapering). Systemic medications or 
topical steroids administered as part of gradual dose reductions are not considered prohibited 
medications. Medications received as such treatments will not be recorded on the concomitant 
medications page but will be recorded on a separate eCRF page.   
 
The number and percentages of subjects with at least one systemic/topical treatment medication 
at the time of study entry will be summarized by treatment group. The number and percentages 
of all medications received as systemic/topical treatments will be summarized by treatment 
group and by ATC level 1 term, ATC level 2 term, and preferred term. All summaries will be 
performed using the Safety population. 
7.2. 
Ocular Surgeries 
All ocular surgeries, including cataract removal, during a subject’s participation in the study will 
be recorded on the eCRF. The number and percentage of subjects with at least one 
surgery/procedure and at least one surgery/procedure for each of the specified reasons 
(recurrence of uveitis, treatment emergent AE, increased IOP, cataract, other) will be 
summarized by treatment group and eye (study, fellow). A frequency distribution for the number 
of surgeries/procedures during the study per subject will also be presented. All summaries will 
be performed using the Safety population and percentages will be based on the total number of 
subjects in the Safety population.  
 
Ocular surgery data, including details on the procedure, eye, study eye designation, start date, 
and reason for the surgery, will be presented in a listing.  
7.2.1 Surgical Intervention to Control Elevated IOP 
The number and percentage of subjects requiring any surgical intervention to control elevated 
IOP will be summarized by treatment group, eye (study, fellow), and time interval. Ocular 
surgeries with a reason of “Increased IOP” will be included in the summary. Incidence will be 
summarized overall through 6 months and for 6 month time intervals through 12 (or 36) months.  
 
A summary of incidence of surgical interventions to control elevated IOP will also be presented 
by geographic region (United States, EMEA, and India) and history of incisional surgery to 
control elevated IOP (History of Incisional Surgery, No History of Incisional Surgery). All 
summaries will be performed using the Safety population. 
 
A listing of all subjects requiring surgical interventions to control elevated IOP will be provided.   
This listing will include details relating to the IOP-lowering surgical intervention (procedure, 
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characteristics including BCVA and IOP,  the last available BCVA and IOP values as of the data 
cut-off, and the date of  first recurrence of uveitis, if any.   
7.2.2 Cataract Surgeries 
The number and percentage of subjects requiring cataract surgery will be summarized by 
treatment group, eye (study, fellow), and time interval. Only eyes which are indicated as phakic 
at study entry will be included for analysis. Ocular surgeries with a reason of “Cataract” will be 
included in the summary. Incidence will be summarized overall through 6 months and for 6 
month time intervals through 12 (or 36) months. All summaries will be performed using the 
Safety population and percentages will be based on the total number of phakic eyes in the Safety 
population. 
7.3. 
Study Treatments 
Fluocinolone acetonide (FA) is the active ingredient in the FAI insert. The FAI insert is provided 
in a sterile preloaded applicator and is administered via injection through the pars plana with a 25 
g needle. The FAI insert contains 0.18 mg FA and delivers FA into the vitreous humor for a 
period of 36 months. 
The sham applicator is an empty 1 mL syringe attached to a blunt needle; it does not contain a 
FAI insert.  
Data related to the study treatment procedure will be presented in a listing.  
7.3.1. Extent of Exposure 
For subjects in the FAI insert group, overall duration of exposure is defined as the total number 
of days a subject is exposed to any study drug and will be presented as the total number of days 
from the injection date (Day 1) to either the FAI insert removal date, for those subjects who have 
the insert removed while in the study, or the last visit date (date of insert removal or last visit - 
the date of injection + 1) as recorded on the End of Study/Early Termination page. If the last visit 
date on the End of Study/Early Termination page is missing, or if a subject is lost to follow-up, 
the latest available visit date will be used. Duration of exposure at Month 6 is defined similarly 
to overall exposure, using either the FAI insert removal date, if removal occurred prior to 
Month 6 visit date, or the Month 6 visit date as the cut off date. If a subject’s Month 6 visit date 
occurs later than the data cut off for the Month 6 analysis (upper limit of Month 6 visit window) 
then the upper limit of the Month 6 visit date will be used as the end date of exposure. A similar 
approach will be used to define duration of exposure at Month 12.   
 
The duration of study participation will be summarized for all subjects. The duration of study 
participation (days) is calculated as date of last visit as recorded on the End of Study/Early 
Termination page – date of Day 1 visit + 1. If the last visit date on the End of Study/Early 
Termination page is missing, or if a subject is lost to follow-up, the latest available visit date will 
be used. Duration of study participation at Month 6 is calculated as the date of Month 6 visit – 
date of Day 1 visit + 1. If a subject’s Month 6 visit date occurs later than the data cut off for the 
Month 6 analysis (upper limit of Month 6 visit window) then the upper limit of the Month 6 visit 
date will be used as the end date of participation. A similar approach will be used to define 
duration of study participation at Month 12.  
 


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The duration of exposure to study drug and duration of study participation up to Month 6 (or 12 
or 36) will be summarized by treatment for all subjects in the Safety population and will be 
presented in a table by summary statistics. The durations of exposure and study participation will 
then be classified into one of the following categories: <= 28 days, 29 to 60 days, 61 to 90 days, 
91 to 180 days, 181 to 270 days, 271 to 360 days, 361 to 540 days, 541 to 720 days, 721 to 900 
days, 901 to 1080 days, and >= 1081 days and will be presented as the number and percentage of 
subjects in each duration category. Percentages will be computed from the number of subjects in 
the Safety population.  
 
A summary of each subject’s exposure and duration of study participation will be presented in a 
listing.  
8. Efficacy Analysis 
PSV-FAI-001 is intended to support submissions to the US Food and Drug Administration 
(FDA) and submissions to other regulatory authorities in the rest of the world (ROW). The FDA 
has requested a definition of recurrence for the primary efficacy analyses that differs from the 
definition of recurrence in PSV-FAI-001. The recurrence definition to be used for the US/FDA is 
outlined in Section 8.1 below.  The FDA definition of recurrence will also be used for all 
supporting sensitivity analyses, subgroup analyses, and exploratory analyses on recurrence of 
uveitis endpoints for the FDA submission.   
 
Efficacy analyses will be performed on both the ITT and PP populations at 6, 12 and 36 months. 
All primary and exploratory efficacy endpoints will be analyzed using the ITT and PP 
populations. The ITT analyses will be considered primary; the PP analyses will be considered 
supportive of the primary analyses on the ITT population.  
8.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the proportion of subjects who have a recurrence of 
uveitis in the study eye within 6 months following treatment.  As noted in section 4, all 
recurrence assessments (including unscheduled visits) on or before the upper limit of the 6 month 
visit window (Day 208) will be considered. Recurrence is captured on the Recurrence of Uveitis 
eCRF page and, for the US/FDA, is defined as: 
 
 An increase in the vitreous haze of > 2 steps (Nussenblatt 1985), compared to baseline or 
any visit time point prior to Month 6 
OR 
 A deterioration in visual acuity of at least 15 letters BCVA associated with recurrence of 
uveitis, compared to baseline or any visit time point prior to Month 6 
Any criterion used to define recurrence must be attributable only to non-infectious uveitis. To 
prevent post-procedural inflammatory reactions from being reported as uveitis recurrences, 
assessments for recurrence of uveitis will begin after the study Day 7 visit.  
 
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8.1.1. Primary Analysis 
 
The primary efficacy analysis will be performed on the ITT population at 6 months and will 
compare the proportion of subjects, in the treatment and control groups, who do not have a 
recurrence of uveitis in the study eye (as defined above) in the 6 months following Day 1. 
 
The primary efficacy analysis will be conducted after all subjects in the study have completed 6 
months of treatment or have discontinued study participation.  
 
The number and percentage of subjects with no recurrence of uveitis in the study eye will be 
presented by treatment group. A continuity-corrected Chi-square test will be used to assess the 
statistical significance of a difference between treatment groups in the primary efficacy analysis. 
Mathematically stated: 
H0: 6 Month Recurrence Free Rate FAI = 6 Month Recurrence Free Rate Sham 
H1: 6 Month Recurrence Free Rate FAI  6 Month Recurrence Free Rate Sham 
The odds ratio for no recurrence (FAI insert/sham) and 95% confidence interval will also be 
presented.   
 
Although the primary analysis will be performed on both the FDA and ROW definitions of 
recurrence, no adjustment of type I error will be performed as the FDA and ROW primary 
efficacy endpoint analyses will be independently evaluated.   
The same inferential analysis employing the same methods as for the primary analysis will be 
performed for the PP population to assess recurrence at Month 6. Additionaly, the same analysis 
will be performed for both the ITT and PP populations to assess recurrence in the exploratory 
analyses conducted at Months 12 and Month 36. For Month 12, any recurrence at or before the 
end of the 12 month visit window (Day 388) will be counted. For Month 36, any recurrence at or 
before the end of the 36 month visit window (Day 1108) will be counted. No adjustment of type 
I error will be performed as these analyses are considered supportive to the primary analysis. 


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8.1.2. Data Imputation 
Data for the primary outcome only (recurrence of uveitis) will be imputed using a 
straightforward method: 
 A subject who has not previously experienced a recurrence and does not have the 
required eye examination data for assessing recurrence at Month 6 (or Month 12 or 
Month 36 for the Month 12 or 36 analyses, respectively) for any reason will be 
considered as having a recurrence. If one or more of the required eye examinations, 
including BCVA and vitreous haze, is not completed at Month 6 (or Month 12 or Month 
36), the subject will be considered as having a recurrence. Reasons for missing 
recurrence data at Month 6 (or 12 or 36) include, but are not limited to: discontinuation 
from the study prior to visit, visit occurred outside of the visit window, and missed visit.   
 A subject who has not previously experienced a recurrence and takes a prohibited 
systemic concomitant medication as defined in Section 9.10.2 of the protocol any time 
during the study prior to Month 6 (or Month 12 or Month 36 for the Month 12 or 36 
analyses, respectively) will be considered as having a recurrence.  
 A subject who has not previously experienced a recurrence and takes a prohibited local 
concomitant medication in the study eye as defined in Section 9.10.2 of the protocol any 
time during the study prior to Month 6 (or Month 12 or Month 36 for the Month 12 or 36 
analyses, respectively) will be considered as having a recurrence.  
 
Systemic medications administered as part of a gradual dose reduction (tapering) (as described in 
Section 9.10.1 of the protocol) will not be considered prohibited medications for the analysis of 
the primary endpoint. For the analysis of the primary endpoint for US/FDA, topical steroids will 
not be considered a prohibited medication. 
 
The prohibited medication data (based on preferred terms and/or ATC codes) will be reviewed 
and medications will be categorized as either having a potential impact on the efficacy 
assessments (consistent with the US/FDA definition of the primary endpoint) or no impact on the 
efficacy assessments. Only prohibited medications determined to have a potential impact on 
efficacy assessments will be taken into consideration for data imputation. The list of prohibited 
medications which will result in an imputed recurrence of uveitis value, for either eye, will be 
identified prior to each database lock. Note: although local medications are permitted in the 
fellow eye, in order to ensure consistency in analysis between the study eye and fellow eye, the 
same list of medications prohibited in the study eye, including local medications, will be 
considered “prohibited” for the fellow eye for the purposes of recurrence imputation.  
 
A listing of subjects with missing recurrence information at Month 6 (or Month 12 or Month 36 
for the Month 12 or 36 analyses, respectively) will be provided. All available recurrence data for 
these subjects will be included in the listing.  
8.1.3. Sensitivity Analyses  
In addition to the conservative imputation for the US/FDA primary efficacy endpoint detailed in 
Section 8.1.2, the following sensitivity analyses of the primary efficacy endpoint will be 
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 The primary outcome will be imputed exactly as in Section 8.1.2 except that a subject 
imputed as having a recurrence because of missing data at Month 6 (or Month 12 or 
Month 36) for any reason will be considered as NOT having a recurrence. Inferential 
analysis employing the same methods as for the primary analysis will be performed. 
 A “tipping point” analysis will be performed.  This analysis will begin by using the 
following imputations associated with missing data at Month 6 (or Month 12 or 
Month 36) for any reason: FAI insert treated subjects will be considered as having a 
recurrence, and sham treated subjects will be considered as NOT having a recurrence.  
The analysis will proceed one imputed FAI insert treated subject at a time, assuming 
that this given subject will be considered as NOT having a recurrence.  All other 
imputations stated in Section 8.1.2 will be performed during this “tipping point” 
analysis.  Inferential analysis employing the same methods as for the primary analysis 
will be performed at each step of the “tipping point” assessment. 
 
Additionally, for missing data due to any reason, sensitivity analyses will be conducted by using 
multiple imputation (MI) methods. The list of subjects who will have their Month 6 (or 12 or 36) 
value imputed using MI methods will be determined prior to each database lock. A fully 
conditional specification (FCS) imputation method will be used to impute missing recurrence 
values. Five imputations will be performed to obtain five complete data sets. The volume of 
missing data will be assessed prior to unmasking at Month 6 and the number of imputations may 
be increased, if necessary. The SAS procedure MI will be used to generate the imputed data sets. 
The following variables will be included in the imputation model: recurrence, age, gender, 
treatment group, systemic treatment at study entry (stratification factor), duration of disease 
(years) in the study eye, number of recurrences in study eye within the 12 months prior to 
screening, and bilateral uveitis history (yes/no).  The imputed datasets will be analyzed by a 
logistic regression model with recurrence as the dependent term and treatment as the independent 
term.  Using the SAS procedure MIANALYZE, results from the logistic regression analysis of 
the five imputed data sets will be combined to obtain overall estimates [SAS/STAT User Guide, 
version 9.3]. Additional details are provided in Appendix 13.2. Note: for this sensitivity analysis, 
subjects who have not previously experienced a recurrence and who take prohibited medications  
prior to the time point of interest will have their Month 6 (or 12 or 36) value imputed as a 
recurrence as described in Section 8.1.2.     
 
The primary efficacy endpoint will be also analyzed with logistic regression with recurrence as 
the dependent term and treatment as the independent term, and including systemic treatment at 
study entry (stratification factor) as a covariate. 1 
8.1.4. Subgroup Analyses 
Subgroup analyses, using descriptive statistics only, will be performed on the US/FDA primary 
efficacy endpoint for the ITT population at Month 6. Analyses will be performed to determine 
the treatment effect within specific subgroups of interest, and to determine if the treatment effect 
                                                 
1 These analyses respond  to guidance received from FDA in its correspondence to pSivida dated September 22, 
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is consistent across different subgroup levels. Subgroups will be defined on the basis of study 
eye baseline characteristics, including: 
 Severity of macular edema [CSFT < 300 microns, CSFT >= 300 microns] 
 Duration of disease [< 2 years, 2 to 5 years, > 5 years] 
 Lens status [Phakic, Aphakic, Pseudophakic] 
 Intraocular pressure [10 to 15 mmHg, >15 to 21 mmHg] 
 History of incisional surgery to control elevated IOP [History, No History]  
 Presence/absence of vitrectomy 
 BCVA [<= 49 letters, > 49 letters]  
 Randomization strata [Not receiving systemic treatment, Receiving systemic treatment – 
corticosteroid therapy, Receiving systemic treatment – immunosuppressive therapy] 
 
Subgroup analyses will also be performed based on region [US, EMEA, India].  
 
Additionally, subgroups will be defined based on IOP lowering medication or surgery received 
in the study eye, as follows:   
 
 Use of IOP lowering medication [No IOP lowering medication, Required IOP lowering 
medication] 
 Surgical Intervention to Control Elevated IOP [No surgical intervention, Required 
surgical intervention] 
 
IOP lowering medication status will be based on a subject’s use of any IOP lowering medication 
in the study eye up to the time point of interest (Month 6, 12 or 36). Surgical intervention status 
will be defined in a similar manner.  
8.2. 
Exploratory Efficacy Endpoints  
The proportion of subjects with recurrence in the study eye within 12 and 36 months will be 
analyzed using the same inferential analysis employing the same methods as for the primary 
analysis as noted in Section 8.1.1.  Sensitivity analysis will also be performed for the proportion 
of subjects with recurrence in the study eye within 12 and 36 months as noted in section 8.1.3. 
 
The following endpoints will be analyzed for the ITT and PP populations employing descriptive 
statistics only:  
 Proportion of subjects in each treatment group who have a recurrence of uveitis in the 
fellow eye (within 6 months, within 12 months and within 36 months) 
 Mean change from baseline in BCVA letter score in the study eye in each treatment 
group (at 6 months, 12 months and 36 months) 
 Number of recurrences of uveitis in each treatment group (within 6 months, within 
12 months and within 36 months) 
 Time to recurrence of uveitis in study eye in each treatment group (within 6 months, 
within 12 months and within 36 months) 
 Number of adjunctive treatments required to treat recurrences of uveitis in each treatment 
group (within 6 months, within 12 months and within 36 months) 


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 Resolution of macular edema, as measured by OCT imaging (at 6 months, 12 months and  
36 months) 
 
Exploratory analyses will use the US/FDA definition of recurrence of uveitis No missing data 
will be imputed other than as noted in Section 8.1.2.  The data imputation method will be applied 
to recurrence of uveitis in the fellow eye values in the same manner as the study eye, with the 3rd 
criteria revised to consider use of prohibited local medications in the fellow eye, instead of the 
study eye.  
 
The number and percentage of subjects with a recurrence of uveitis in the study eye within 
12 months and within 36 months and with a recurrence of uveitis in the fellow eye within 6 
months, within 12 months and within 36 months will be presented by treatment group.  
 
ETDRS letter score absolute value and change from baseline at Month 6 (and 12 and 36) will be 
described for each treatment group using descriptive statistics. 
  
For each subject and eye (study, fellow), the number of recurrences through Month 6, 12 and 36 
will be calculated. Recurrences imputed at Month 6, 12 or 36 due to missing data as per  
Section 8.1.2 will be considered a recurrence for this calculation. The number of recurrences per 
subject and eye (study, fellow) will be described using descriptive statistics as well as the 
number and percentage of subjects by category (0, 1, 2, 3, 4, 5, >5). Additionally the total 
number of recurrences summed across all subjects, all study eyes and all fellow eyes will be 
presented by treatment group. 
 
The time to first recurrence of uveitis within 6 months is calculated as the number of days 
between the date of injection (Day 1) and the visit date of the first reported recurrence of uveitis 
in the study eye. Subjects who do not experience a recurrence of uveitis within 6 months will be 
censored at the date of their Month 6 visit. The time to first recurrence of uveitis within 12 (or 
36) months will be calculated in a similar manner, censoring at the date of a subject’s Month 12 
(or 36) visit if the subject does not experience a recurrence of uveitis within 12 (or 36) months. 
Recurrences imputed at Month 6 (or Month 12 or Month 36) due to missing data as per Section 
8.1.2 will be considered a recurrence in the time to recurrence analysis. Median time to 
recurrence and the 95% confidence interval for the median will be summarized by treatment 
group and randomization strata. The Kaplan-Meier estimated probabilities of recurrence will also 
be presented for monthly intervals through 36 months. Since time to recurrence is calculated in 
days, the monthly intervals will be defined based on 30 days = 1 month. Kaplan-Meier plots for 
time to first recurrence of uveitis will also be presented.  
 
The number of adjunctive treatments, including systemic steroids or immunosuppressants, 
intra/peri-ocular steroids, and topical steroids, will be determined using medications/therapies 
recorded on the Concomitant Medications page with start/end dates within the given time period 
(6, 12 or 36 months).  The number and percentage of subjects by number of adjunctive 
treatments will be presented by treatment group and category of adjunctive treatment. The 
intra/peri-ocular steroids and topical steroids will also be presented by eye (study, fellow). 
Multiple doses of the same medication which are part of one treatment regimen will be counted 
as one adjunctive treatment for the purposes of analysis.  


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Resolution of macular edema will be summarized using a shift table comparing the presence 
(Yes, No, Not Evaluable) of macular edema at Month 6 (and 12 and 36) to the baseline response 
by eye (study, fellow) and treatment group.  
9. Safety Analysis 
Safety analyses will be performed on the Safety population at 6, 12 and 36 months. Subjects who 
are randomized but do not receive treatment will not be included in safety tabulations but have 
all safety data listed only.  Percentages for safety summaries based on the number of subjects 
with a given event or attribute will be based on the number of subjects who were treated 
(including sham treatment).  
9.1. 
Adverse Events 
A treatment-emergent AE (TEAE) is defined as an AE that meets any of the following 
conditions: 
 begins on or after the date of injection (Day 1); 
 begins before the date of injection (Day 1) and worsens in severity on or after the date of 
injection (Day 1); 
 is completely missing a start date and end date; 
 is completely missing a start date and the end date is on or after the date of injection (Day 1). 
 
For the purpose of inclusion in TEAE tables, incomplete AE start and end dates will be imputed 
as follows: 
Missing onset dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
 
UK-MMM-YYYY: If the month and year are different from the month and year of the 
date of injection, assume 01-MMM-YYYY. If the month and year are the same as the 
month and year for the date of injection, and the end date (after any imputation) is on or 
after the date of injection, then assume the date of injection (Day 1). If the month and 
year are the same as the date of injection, and the end date (after any imputation) is prior 
to the date of injection, then assume the end date for the start date.  
 
DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of the date of 
injection, assume 01-JAN-YYYY of the collected year. If the year is the same as the date 
of injection year, and the end date (after any imputation) is on or after the date of 
injection, then assume the date of injection (Day 1). If the year is the same as the date of 
injection, and the end date (after any imputation) is prior to the date of injection, then 
assume the end date for the start date.  
 
Missing end dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
 UK-MMM-YYYY: Assume the last day of the month; 
 DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY. 
 


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All adverse events will be classified by System Organ Class and Preferred Term (PT) according 
to the Medical Dictionary for Regulatory Activities (MedDRA, Version 15.1 or higher). 
 
An overview summary of the number and percentage of subjects with any TEAE, serious TEAE, 
treatment-related TEAE, treatment-related serious TEAE, TEAE leading to FAI insert removal, 
TEAE leading to study discontinuation, and AE leading to death will be provided by treatment 
group.  
 
All AE summaries will be provided for ocular events and non-ocular events, separately. Ocular 
event tables will be presented by eye (study, fellow).    
 
All AEs will be presented in a listing. 
9.1.1. Incidence of Adverse Events 
Summaries of the total number of TEAEs and the number and percentage of subjects with at 
least one TEAE will be provided by treatment group and overall. Treatment-emergent AEs will 
be presented by System Organ Class and PT. At each level of subject summarization, a subject is 
counted once if the subject reported one or more events. Percentages will be calculated out of the 
number of subjects in the Safety population.  
 
The summary of TEAEs will be presented in descending order from the System Organ Class 
with the highest total incidence (that is, summed across all treatment groups) to the System 
Organ Class with the lowest total incidence. If the total incidence for any two or more System 
Organ Classes is equal, the System Organ Classes will be presented in alphabetical order. Within 
each System Organ Class, the PTs will be presented in alphabetical order.  
 
A separate summary of protocol defined ocular AEs, overall and by criteria, will be provided. 
This summary will include the following ocular events, as reported on the AE eCRF page: 
 decrease in visual acuity of at least ≥ 15 letters or ≥ 3 lines from the previous 
measurement of visual acuity 
 moderate or severe (grade 3 or 4) ocular findings compared to the last ophthalmic 
examination 
 worsening of ≥ 2 steps in anterior chamber cell count or vitreous haze, compared to the 
last ophthalmic examination 
 increase in IOP of ≥ 10 mmHg at two visits at least 1 week apart or an increase in IOP to 
≥ 25 mmHg 
9.1.2. Relationship of Adverse Events to Study Treatment 
A summary of TEAEs by relationship to study treatment will be presented in a table by incidence 
of occurrence. The investigator will provide an assessment of the relationship of the event to the 
study treatment. The possible relationships are “Unrelated”, “Possibly Related”, and “Probably 
Related”. In the TEAE relationship table, if a subject reports multiple occurrences of the same 
TEAE, only the most closely related occurrence will be presented. Treatment-emergent AEs that 
are missing a relationship will be presented in the summary table as “Probably Related” but will 
be presented in the data listing with a missing relationship. Percentages will be calculated based 
on the number of subjects in the Safety population. 


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The TEAE data will be categorized and presented by System Organ Class, PT, and relationship 
in a manner similar to that described in Section 9.1.1.  
9.1.3. Severity of Adverse Event 
A summary of TEAEs by severity will be presented in a table. The severity that will be presented 
represents the most extreme severity captured on the eCRF page. The possible severities are 
“Mild,” “Moderate,” and “Severe.”  In the TEAE severity table, if a subject reported multiple 
occurrences of the same TEAE, only the most severe will be presented. Treatment-emergent AEs 
that are missing severity will be presented in tables as “Severe” but will be presented in the data 
listing with a missing severity. Percentages will be calculated out of the number of subjects in 
the Safety population. 
 
A summary of TEAEs related to study treatment by severity will be presented in a table. Events 
with a relationship if “Possibly Related” and “Probably Related” will be considered related to 
study treatment and included in this summary. 
 
The TEAE data will be categorized and presented by System Organ Class, PT, and severity in a 
manner similar to that described in Section 9.1.1. 
9.1.4. Serious Adverse Events 
Serious treatment-emergent adverse events (SAEs) will be presented in a table. Treatment-
emergent SAEs by severity will be presented in a table. At each level of subject summarization, a 
subject is counted once if the subject reported one or more events. Percentages will be calculated 
out of the number of subjects in the Safety population.  
 
The treatment-emergent SAE data will be categorized and presented by System Organ Class and 
PT in a manner similar to that described in Section 9.1.1 and by severity as described in Section 
9.1.3. 
 
A separate summary of protocol defined SAEs, overall and by criteria, will be provided. This 
summary will include the following sight-threatening ocular events, as reported on the AE/SAE 
eCRF page: 
 An AE which causes a decrease in visual acuity of ≥ 30 letters or ≥  6 lines from the most 
recent previous measurement of visual acuity, lasting more than 1 hour  
 An AE which causes a decrease in visual acuity to light perception or worse, lasting more 
than 1 hour 
 An AE which requires surgical intervention (e.g., conventional surgery, vitreous tap or 
biopsy with intravitreal injection of anti-infectives, or laser or retinal cryopexy with gas) 
to prevent permanent loss of sight 
 An AE which is associated with severe intraocular inflammation (i.e., 4.0 anterior 
chamber cell score, 4+ flare or 4+ vitritis) 
 Two consecutive IOP measurements of 30 mmHg or higher taken at least 72 hours apart 
when a subject is already being treated with two glaucoma medications 
 An IOP < 6 mmHg requiring medical intervention 


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 An AE which in the opinion of the investigator requires medical or surgical intervention 
to prevent permanent loss of sight 
9.1.5. Adverse Events Leading to FAI Insert Removal 
A summary of TEAEs with an action taken with study treatment of “FAI Insert Removal” will be 
presented in a table. At each level of subject summarization, a subject is counted once if the 
subject reported one or more events. Percentages will be calculated out of the number of FAI 
insert subjects in the Safety population.  
 
The summary of TEAEs with an action taken with study treatment of “FAI Insert Removal” will 
be presented in descending order of frequency from the System Organ Class with the highest 
total incidence (that is, summed across all treatment groups) to the System Organ Class with the 
lowest total incidence. Within each System Organ Class, the PTs will be presented in 
alphabetical order. 
9.1.6. Adverse Events Leading to Study Discontinuation  
All subjects who have an AE where the answer to “Was Subject Terminated from study due to 
this AE?” is “Yes” will be presented in a listing.   
9.1.7. Death 
All subjects who have an AE with an outcome of “Fatal” will be presented in a listing.  
9.1.8. Adverse Events of Special Interest 
A summary of TEAEs of cataract and elevated IOP will be presented in a table by treatment 
group and overall. Events will be included in the summary based on a list of preferred terms for 
each event category. At each level of subject summarization, a subject is counted once if the 
subject reported one or more events. Percentages will be calculated out of the number of subjects 
in the Safety population. Within each event category, the PTs will be presented in alphabetical 
order.  
 
A summary of ocular TEAEs which are considered complications of IOP lowering medications 
to control IOP will be presented by treatment group and overall. Events will be included in the 
summary based on a list of preferred terms and an onset date on or after the date of first use of 
any IOP lowering medication. The list of PTs will be generated based on the most common 
adverse events associated with the IOP lowering medications used.     
 
A summary of ocular TEAEs which are considered complications of surgical interventions to 
control IOP will be presented by treatment group and overall. Events will be included in the 
summary based on a list of preferred terms and an onset date on or after the date of surgical 
intervention. A similar summary will be presented for complications of cataract surgeries.  
9.2. 
Ophthalmic Examination 
All ophthalmic examinations are performed on both eyes.  


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9.2.1. Best-corrected Visual Acuity (BCVA) 
Best-Corrected Visual Acuity will be measured according to the standard procedure developed 
for ETDRS at 4 meters or 3 meters if the electronic (E)-ETDRS system is employed. For patients 
who are illiterate of not familiar with the English alphabet, BCVA will be determined using the 
Tumbling E ETDRS charts. Corrected-distance VA is reported as the number of letters read 
correctly by the subject. The Snellen Fraction will also be recorded. If the subject is unable to 
read any letters at 4 meters or 1 meter, the investigator will assess the subject’s ability to count 
fingers, recognize hand motion, or light perception.   
 
A summary table presenting the observed values and changes from baseline in BCVA (letters) 
will be presented by eye (study, fellow), treatment group and overall for subjects in the Safety 
population. Changes from baseline to each scheduled post-baseline visit will be presented. In 
addition, a categorical summary of change from baseline in BCVA will present the letter change 
at Month 6 (or Month 12 or Month 36) and the maximum letter change at any time point up to 
Month 6 (or Month 12 or Month 36), including categories of ≥ 15 letters lost, ≥ 10 letters lost, ≥ 
5 letters lost, no change, ≥ 5 letters gained, ≥10 letters gained, and ≥ 15 letters gained.  
 
The BCVA summaries will also be presented by eye for the following subgroups: 
 IOP lowering medication [No IOP lowering medication, Required IOP lowering 
medication] 
 Surgical Intervention to Control Elevated IOP [No surgical intervention, Required 
surgical intervention] 
 Lens status at Baseline [Phakic, Aphakic, Pseudophakic] 
 
IOP lowering medication status will be based on a subject’s use of any IOP lowering medication 
up to the time point of interest (Month 6, 12 or 36). Surgical intervention status will be defined in 
a similar manner.  Subgroups will be defined per eye and a subject’s study eye may belong to a 
different subgroup than the fellow eye. 
  
For subjects with phakic lens status at study entry who undergo cataract surgery while in the 
study, the change in BCVA (letters) from the last BCVA measurement prior to surgery to the 
first BCVA measurement after surgery will be summarized by treatment and eye. In addition, a 
summary of change from baseline in BCVA (letters) at Month 6 (or 12 or 36) will be presented 
by treatment for subjects with phakic eyes at study entry who undergo cataract surgery prior to 
Month 6 (or 12 or 36) vs. subjects with a lens status of pseudophakic at study entry.  
   
BCVA data will be presented in a listing.  
9.2.2. Intraocular Pressure (IOP) 
Applanation tonometry (preferable Goldman) will be used for IOP measurements, where the 
value recorded on the eCRF is an average of 3 measurements. On Day 1, this assessment will be 
performed pre- and post-administration of study treatment.  
 
A summary table presenting the observed values and changes from baseline in IOP (mmHg) will 
be presented by eye (study, fellow), treatment group and overall for subjects in the Safety 


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population who received treatment. Changes from baseline to each scheduled post-baseline visit, 
as well as the Day 1 post-administration of study treatment, will be presented.  
 
The number and percentage of patients with an IOP measurement > 21 mmHg at any post-
administration assessment will be presented for each treatment group and overall by eye (study, 
fellow). Incidence will be summarized overall (through 6, 12 or 36 months) and for 3-month 
time intervals through Month 6. For Month 12 analysis, the incidence will be summarized for 3-
month intervals through Month 12. For Month 36 analysis, the incidence will also be 
summarized for 6-month time intervals from Month 12 through Month 36.  
 
Additionally, the number and percentage of patients with an IOP measurement meeting any of 
the IOP elevation criteria at any post-administration assessment and by visit will be presented for 
each treatment group and overall by eye (study, fellow). The IOP elevation criteria include:  
 Increase in IOP from baseline of > 5 mmHg  
 Increase in IOP from baseline of ≥ 12 mmHg 
 IOP measurement > 25 mmHg 
 IOP measurement > 30 mmHg 
 
IOP data will be presented in a listing. 
9.2.3. Dilated Indirect Ophthalmoscopy 
The investigator will assess the status (Normal, Abnormal – Clinically Significant, Abnormal – 
Not Clinically Significant) of the vitreous, macula, retina, optic nerve, choroid, and retinal 
periphery. On Day 1, this assessment will be performed pre- and post-administration of study 
treatment. Post-administration of study treatment, the investigator will assess the adequacy of the 
central retinal artery perfusion and indicate the presence of any complications. Data from the 
indirect ophthalmoscopy examination will be presented in a listing.   
9.2.4. Slit Lamp Examination 
The investigator will assess any changes in lens or cataract status and the status (Normal, 
Abnormal – Clinically Significant, Abnormal – Not Clinically Significant) of the conjunctiva, 
cornea, iris, anterior chamber, and posterior chamber.  
 
A summary table presenting the number and percentage of subjects with a change in lens/cataract 
status since screening or a worsening of an existing cataract since the previous visit will be 
presented by eye (study, fellow), baseline lens status, treatment group and overall for subjects in 
the Safety population with a phakic or pseudophakic lens status at study entry for the given eye.  
 
Data from the slit lamp examination will be presented in a listing.   
9.2.5. Vitreous Haze and Anterior Chamber Cells 
Indirect ophthalmoscopy will be performed for each eye with pupil dilation.  The following scale 
(Nussenblatt 1985) will be used to define the extent of vitreous haze:  


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Absent 
Clear view of optic disc, retinal vessels and nerve fiber layer 
Trace 
Slight blurring of optic disc margin and of normal striations and reflex 
of nerve fiber layer 
1+ 
Mild blurring of optic disc margin and slight loss of retinal vessel 
definition 
2+ 
Moderate blurring of optic disc margin and loss of retinal vessel 
definition 
3+ 
Optic nerve head and large vessels visible but borders quite (very) 
blurry 
4+ 
Optic nerve head obscured 
 
Anterior chamber cells will be measured using a Haag/Streit or similar slit lamp at high 
magnification (1.6 X) 1-mm beam. Assessment will be made using the following scale (Jabs 
2005). 
 
Field size: 1 mm by 1 mm slit beam 
0 
<1 cells/hpf 
0.5+ 
1-5 cells/hpf 
1+ 
 
6-15 cells/hpf 
2+ 
16-25 cells/hpf 
3+ 
 
26-50 cells/hpf 
4+ 
>50 cells/hpf 
 
Frequency distributions of the vitreous haze and anterior chamber cells grading at each 
scheduled visit will be summarized in a table by eye (study, fellow), treatment group, and overall 
for subjects in the Safety population.   
 
All vitreous haze and anterior chamber cell data will be presented in a listing. 
9.3. 
Humphrey 24-2 Visual Field Test 
A summary table presenting the observed values and changes from baseline will be presented for 
mean deviation (dB) by eye (study, fellow), treatment group and overall for subjects in the 
Safety population who received treatment. Changes from baseline to each scheduled post-
baseline visit will be presented. Visual field test data will be presented in a listing.  
9.4. 
Optical Coherence Tomography (OCT) 
The OCT assessments will evaluate the central foveal thickness (CFT), central subfield thickness 
(CFST), total volume of the central subfield, and the presence of macular edema, cysts, intra-
retinal fluid, sub-retinal fluid, and fibrosis for both eyes.  
 
A summary table presenting the observed values and changes from baseline will be presented for 
CFT (microns), CFST (microns), and total volume of the central subfield (mm3) by eye (study, 
fellow), treatment group and overall for subjects in the Safety population. Changes from baseline 
to each scheduled post-baseline visit will be presented.  
 


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The categorical data from the OCT assessment will be summarized in a shift table comparing the 
presence (Yes, No, Not Evaluable) of each symptom noted above at each post-baseline visit to 
the baseline response by eye (study, fellow), treatment group, and overall for subjects in the 
Safety population. Shifts from baseline to each scheduled post-baseline visit will be presented.   
 
All OCT data will be presented in a listing. 
9.5. 
Subjective Ocular Tolerability and Discomfort Assessment  
Subjects will assess ocular tolerability using a subjective scale (Scoville 1985).  A visual 
analogue scale is performed by asking subjects to indicate on an unmarked 100 mm line the 
intensity of their irritation. A mark of '0' represents no sensation while '100' indicates the worst 
imaginable irritation. The location of the mark on the line then is measured with a mm ruler to 
provide a numeric score. A summary table presenting the observed values and changes from 
baseline in irritation intensity (mm) will be presented by eye (study, fellow), treatment group and 
overall for subjects in the Safety population. Changes from baseline to each scheduled post-
baseline visit will be presented. As part of the ocular tolerability assessment, subjects will be 
asked to indicate which eye feels more uncomfortable. The responses (no difference, study eye, 
fellow eye) will be summarized by visit, treatment group and overall for subjects in the Safety 
population. 
 
Subjects will also assess discomfort using the following subjective scale (Maca 2010).  This 
parameter will consist of a single overall assessment of the subject’s discomfort considering 
superficial pain, foreign body, or gritty sensation, itching, burning, and other forms of non-
specific discomfort. 
Grade 0: Absent 
Grade 0.5: Very mild 
Grade 1: Mild 
Grade 2: Moderate 
Grade 3: Severe 
Grade 4: Intolerable 
The categorical data from the discomfort assessment will be summarized in a shift table 
comparing the grade at each post-baseline visit to the baseline grade of discomfort by eye (study, 
fellow) and treatment group for subjects in the Safety population who received treatment. Shifts 
from baseline to each scheduled post-baseline visit will be presented.   
 
All subjective ocular tolerability and discomfort data will be presented in a listing. 
9.6. 
Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a local laboratory at the Screening visit only. 
Laboratory results will not be included in the clinical database. Any clinically significant 
laboratory values at Screening will be entered into the subject’s medical history.   
 
The laboratory testing eCRF data, including confirmation that the lab tests were performed, an 
explanation if they were not performed, and whether there were any clinically significant values, 
will be presented in a listing.  


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Female subjects of child-bearing potential will have urine pregnancy tests conducted throughout 
the study. Any subjects with positive pregnancy test results at any time during the study will be 
presented in a listing. The listing will also include the subject’s fertility status collected at the 
Screening visit.  
9.7. 
Vital Sign Measurements 
Summary tables will be presented for vital sign data, including sitting systolic blood pressure 
(mmHg), sitting diastolic blood pressure (mmHg) and pulse (bpm), by treatment group and 
overall for subjects in the Safety population. Observed results at each visit and changes from 
baseline to each scheduled post-baseline visit will be presented. All vital sign data by subject will 
be presented in a listing. 
9.8. 
Physical Examination 
Any abnormalities noted during the physical examination will be presented in a listing for all 
subjects.  
10. Interim Analysis 
No interim analysis is planned for this study. The primary analysis and all other efficacy and 
safety analyses will be conducted at the Month 6 database lock; i.e., after all subjects have 
completed the Month 6 visit or have been discontinued from the study prior to this visit. Analysis 
of the study data through Month 12 and the complete study data (through Month 36) will be 
performed after all subjects have either completed the Month 12 or Month 36 visit, or have been 
discontinued from the study prior to the respective visit, Month 12 or Month 36. 
11. Changes in the Planned Analysis 
11.1. Changes from the Protocol Made Prior to unmasking 
Laboratory assessments will not be presented by descriptive statistics as stated in the protocol.  
The primary efficacy analysis will be performed using the US/FDA definition of recurrence and 
not the definition in the protocol. For data imputation of the US/FDA primary endpoint, topical 
steroids will not be considered a prohibited medication that would result in imputation of 
recurrence of uveitis.   
11.2. Changes Made After Umasking 
Clarifying text was added to section 8.1 to confirm that all recurrences through the end of the 6 
month visit window (Day 208) are counted for the primary efficacy variable of recurrence at 6 
months. Additional clarifying text was added to section 8.1.1 to confirm the visit windows for 
which any recurrence will be counted for the analyses at month 12 and 36. 
 
12. References 
Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) 
Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of 
the First International Workshop, Am J Ophthalmol 2005; 140: 509-16. 
 


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Maca SM, Amon M, Findl O, Kahraman G, Barisani-Asenbauer T. Efficacy and tolerability of 
preservative-free and preserved diclofenac and preserved ketorolac eyedrops after cataract 
surgery. Am J Ophthalmol. 2010; 149: 777-784. 
 
Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology 1985; 92: 467–71. 
 
Retisert Prescribing Information (June 2011). 
 
SAS/STAT User’s Guide, version 9.2., SAS Institute, Inc., Cary, North Carolina. 
 
Scoville B, Krieglstein GK, Then E, Yokoyama S, Yokoyama T. Measuring drug-induced eye irritation: a 
simple new clinical assay. J Clin Pharmacol 1985; 25: 210–218. 
 
13. Appendices 
 


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13.1. Schedule of Study Procedures and Assessments 
 
Assessments 
Screening 
Day 
1 
Day 
7 
Day 
28 
Months 
2, 3 
Months 
6, 9, 12, 
18, 24, 
30, 36 
Timing/Interval 
-30 to 0 
1 
±2D 
±3D 
±7D 
±28D 
Medical/Ophthalmic History 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Pregnancy Testb 
X 
X 
 
 
 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
Clinical Labsd 
X 
 
 
 
 
 
Ophthalmic Examinatione 
X 
X 
X 
X 
X 
X 
Visual Fieldf 
X 
 
 
 
 
X 
OCT 
 
X 
 
 
X 
X 
Physical Exam 
X 
 
 
 
 
 
Subjective Ocular Tolerability & Discomfort Assessment 
X 
X 
X 
X 
X 
X 
FAI Insert Placement or Sham Injection 
 
X 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
                                                 
b Females of child-bearing potential only: urine test conducted only at Screening, Day 1, Month 12, Month 24 and Month 36. 
c Includes systolic/diastolic blood pressure and pulse rate after subject is in the sitting position for at least 5 minutes.  Height and weight at Screening 
only. 
d Hematology; ESR; serum chemistry; urinalysis; HIV and syphilis serology testing; TB testing. 
e Ophthalmic examination includes BCVA, IOP [recorded as the mean of three measurements], dilated indirect ophthalmoscopy, and anterior, 
posterior, and intermediate slit lamp examinations. 
f Conducted only at Months 12, 24 and 36. 


pSivida Corp. 
 
 
             Final Statistical Analysis Plan, Version 4.1 
PSV-FAI-001 
 
 
                       Date Issued: 05JAN2017 
 
  
 
 
 
30
Assessments 
Screening 
Day 
1 
Day 
7 
Day 
28 
Months 
2, 3 
Months 
6, 9, 12, 
18, 24, 
30, 36 
AEs 
 
X 
X 
X 
X 
X 
 


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13.2 
SAS Code for Multiple Imputation Method 
 
A fully conditional specification (FCS) imputation method will be used to impute missing 
recurrence values at Month 6 (or 12 or 36). The following SAS code will be used to 
generate the imputed data sets: 
 
PROC MI DATA = <derived dataset> SEED = xxxxxx NIMPUTE = 5; 
 
CLASS NoRecurrence Gender TrtGroup StratFactor BilateralUveitis; 
 
FCS DISCRIM (NoRecurrence Gender BilateralUveitis TrtGroup)  
        LOGISTIC (StratFactor/ ORDER=INTERNAL) 
        REG (Age DurDisease NumRecur); 
 
VAR Age Gender DurDisease StratFactor NumRecur BilateralUveitis TrtGroup  
         NoRecurrence; 
RUN; 
 
where 
 
NoRecurrence indicates whether the subject completed through Month 6 (or 12 or 36) 
without a recurrence of uveitis in the study eye (1 = Yes, 0 = No),  
Age is the subject’s age in years, 
BilateralUveitis indicates whether the subject has a history of bilateral uveitis (1 = Yes, 0 = 
No).  
DurDisease is the duration of disease (years) in the study eye, 
Gender (1 = Male, 2 = Female), 
NumRecur is the number of recurrences in the study eye within the 12 months prior to 
Screening, 
StratFactor indicates the use of systemic treatment at study entry (1 = Not receiving 
systemic treatment, 2 = Receiving systemic treatment – corticosteroid therapy, 3 = 
Receiving systemic treatment – immunosuppressive therapy),  
TrtGroup is the treatment variable. 
 
The following model will be fit in the SAS procedure LOGISTIC to analysis the imputed 
datasets:  
 
Ods Output ParameterEstimates = parms CovB = covb; 
PROC LOGISTIC DATA = < MI dataset >  
 
BY _IMPUTATION_; 
 
CLASS NoRecurrence TrtGroup (REF=last) \ PARAM=ref; 
 
MODEL NoRecurrence (event = ‘1’) = TrtGroup/ covb; 
RUN; 
 


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Then the SAS procedure MIANALYZE will be used to obtain the overall estimates, using 
the ParameterEstimates and CovB ods output datasets from the LOGISTIC procedure. The 
following code will be used:  
 
Ods Output ParameterEstimates = MIparms; 
PROC MIANALYZE PARMS(classvar=classval)= parms 
 
 
 
COVB (effectvar=stacking)= covb; 
 
CLASS TrtGroup; 
 
MODELEFFECTS intercept TrtGroup; 
RUN;  
 
The odds ratio and 95% confidence interval will be calculated by taking the exponentiation 
of the ESTIMATE, LCLMean and UCLMean variables where PARM = ‘TrtGroup’ in the 
MIparms dataset. Variable Probt from the same observation will be used for the p-value.  
 


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PSV-FAI-001                                                                                                                                                           Date Issued: 05JAN2017 
 
 
 
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13.3 
Note for FDA Reviewers 
 
The statistical analysis plan (SAP) for PSV-FAI-001 has been revised in accordance with 
guidance provided by FDA to pSivida regarding: 1) the definition of the primary endpoint; 
2) the use of different SAPs for different regions in the world.  
 
Specifically, FDA provided the following guidance to pSivida:  
 
1. Definition of primary endpoint:  
 
FDA Response to Question 1b: 
No; the Agency considers anterior and posterior uveitis to be separate indications. 
While the inclusion criteria for study eye enrollment may include eyes with a 
“history of noninfectious uveitis affecting the posterior segment of the eye with or 
without anterior uveitis ≥ 1 year duration;” the efficacy endpoint of “a ≥ 2 step 
increase in the number of cells in anterior chamber” at 12 months would not be 
acceptable.  
Source:  
This excerpt is derived from FDA correspondence  
 
 
[titled MEMORANDUM OF MEETING MINUTES] 
dated April 10, 2015, providing FDA’s minutes of a Type C meeting 
convened on March 10, 2015 between FDA and pSivida. 
 
In response to FDA’s guidance, pSivida committed to using a revised definition of the 
primary efficacy endpoint that will NOT include “a >2 step increase the number of cells in 
the anterior chamber”. 
 
2. Statistical analysis plans  for different regions in the world:  
 
The Agency stated that the protocol can have different statistical analysis plans for 
the different regions of the world. 
Source:  
This excerpt is derived from FDA correspondence  
 
 
[titled MEMORANDUM OF MEETING MINUTES] 
dated June 5, 2015, providing FDA’s minutes of a Type C meeting  
convened on May 7, 2015 between FDA and pSivida 
 
In response to FDA’s guidance, pSivida has prepared a revised, US-specific statistical 
analysis plan [SAP v3.0 (US)] for PSV-FAI-001. SAP v3.0 (US) uses a revised definition 
of the primary efficacy endpoint that aligns with FDA’s guidance from the March 10, 2015 
type C meeting.  
 


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Note: pSivida has not revised the primary efficacy endpoint in protocol PSV-FAI-001, 
because regulatory authorities in other regions in which the study is being conducted have 
not requested the same change as has been recommended by FDA.  
 
Consequently, pSivida has prepared two SAPs associated with PSV-FAI-001: one for the 
US and one for rest of world (ROW). If requested by FDA, pSivida will submit the ROW 
SAP for FDA’s review.   
 
The major differences between the two SAPs are presented in the following table: 
 
Parameter 
SAP 
ROW 
US/FDA 
Primary 
efficacy 
endpoint 
 
The primary efficacy endpoint is defined as the proportion 
of subjects who have a recurrence of uveitis in the study 
eye within 6 months following treatment.  Recurrence is 
captured on the Recurrence of Uveitis eCRF page and is 
defined as: 
 
A > 2 step increase in the number of cells in 
the anterior chamber per high powered field 
(1.6 X using a 1-mm beam) (Hogan 1959), 
compared to baseline or any visit time point 
prior to Month 6 
OR 
 
An increase in the vitreous haze of > 2 steps 
(Nussenblatt 1985), compared to baseline or 
any visit time point prior to Month 6 
OR 
 
A deterioration in visual acuity of at least 15 
letters BCVA associated with recurrence of 
uveitis, compared to baseline or any visit time 
point prior to Month 6 
Any criterion used to define recurrence must be 
attributable only to non-infectious uveitis. To prevent 
post-procedural inflammatory reactions from being 
reported as uveitis recurrences, assessments for 
recurrence of uveitis will begin after the study Day 7 visit. 
 
The primary efficacy endpoint is defined as the proportion 
of subjects who have a recurrence of uveitis in the study 
eye within 6 months following treatment.  Recurrence is 
captured on the Recurrence of Uveitis eCRF page and is 
defined as: 
 
A > 2 step increase in the number of cells in 
the anterior chamber per high powered field 
(1.6 X using a 1-mm beam) (Hogan 1959), 
compared to baseline or any visit time point 
prior to Month 6 
OR 
 
An increase in the vitreous haze of > 2 steps 
(Nussenblatt 1985), compared to baseline or 
any visit time point prior to Month 6 
OR 
 
A deterioration in visual acuity of at least 15 
letters BCVA associated with recurrence of 
uveitis, compared to baseline or any visit time 
point prior to Month 6 
Any criterion used to define recurrence must be 
attributable only to non-infectious uveitis. To prevent 
post-procedural inflammatory reactions from being 
reported as uveitis recurrences, assessments for 
recurrence of uveitis will begin after the study Day 7 visit. 
 
 


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Parameter 
SAP 
ROW 
US/FDA 
Imputed 
recurrence 
 
Data for the primary outcome only (recurrence of uveitis) 
will be imputed using a straightforward method: 
• A subject who has not previously experienced a 
recurrence and does not have the required eye 
examination data for assessing recurrence at Month 
6 ( or Month 12 or Month 36 for the Month 12 or 36 
analyses, respectively) for any reason will be 
considered as having a recurrence. If one or more of 
the required eye examinations, including BCVA, 
vitreous haze, and anterior chamber cells, is not 
completed at Month 6 (or Month 12 or Month 36), 
the subject will be considered as having a 
recurrence. Reasons for missing recurrence data at 
Month 6 (or 12 or 36) include, but are not limited to: 
discontinuation from the study prior to visit, visit 
occurred outside of the visit window, and missed 
visit.   
• A subject who has not previously experienced a 
recurrence and takes a prohibited systemic 
concomitant medication as defined in Section 9.10.2 
of the protocol any time during the study prior to 
Month 6 (or Month 12 or Month 36 for the Month 
12 or 36 analyses, respectively) will be considered 
as having a recurrence.  
• A subject who has not previously experienced a 
recurrence and takes a prohibited local concomitant 
medication in the study eye as defined in Section 
9.10.2 of the protocol any time during the study 
prior to Month 6 (or Month 12 or Month 36 for the 
Month 12 or 36 analyses, respectively) will be 
considered as having a recurrence.  
 
Systemic medications and topical steroids administered as 
part of a gradual dose reduction (tapering) (as described 
in Section 9.10.1 of the protocol) will not be considered 
prohibited medications. Additionally, topical steroids 
administered as part of short term standard treatment 
following an ocular surgical procedure (as described in 
Section 9.10.2 of the protocol) will not be considered 
prohibited medications. 
 
Data for the primary outcome only (recurrence of uveitis) 
will be imputed using a straightforward method: 
• A subject who has not previously experienced a 
recurrence and does not have the required eye 
examination data for assessing recurrence at Month 
6 ( or Month 12 or Month 36 for the Month 12 or 36 
analyses, respectively) for any reason will be 
considered as having a recurrence. If one or more of 
the required eye examinations, including BCVA and 
vitreous haze, and anterior chamber cells, is not 
completed at Month 6 (or Month 12 or Month 36), 
the subject will be considered as having a 
recurrence. Reasons for missing recurrence data at 
Month 6 (or 12 or 36) include, but are not limited to: 
discontinuation from the study prior to visit, visit 
occurred outside of the visit window, and missed 
visit.   
• A subject who has not previously experienced a 
recurrence and takes a prohibited systemic 
concomitant medication as defined in Section 9.10.2 
of the protocol any time during the study prior to 
Month 6 (or Month 12 or Month 36 for the Month 
12 or 36 analyses, respectively) will be considered 
as having a recurrence.  
• A subject who has not previously experienced a 
recurrence and takes a prohibited local concomitant 
medication in the study eye as defined in Section 
9.10.2 of the protocol any time during the study 
prior to Month 6 (or Month 12 or Month 36 for the 
Month 12 or 36 analyses, respectively) will be 
considered as having a recurrence.  
 
Systemic medications and topical steroids administered as 
part of a gradual dose reduction (tapering) (as described 
in Section 9.10.1 of the protocol) will not be considered 
prohibited medications for the analysis of the primary 
endpoint. For the analysis of the primary endpoint, a 
topical steroid will not be considered a prohibited 
medication. Additionally, topical steroids administered as 
part of short term standard treatment following an ocular 
surgical procedure (as described in Section 9.10.2 of the 
protocol) will not be considered prohibited medications.