Drug Utilization Study in Patients Receiving Ozurdex™ (Dexamethasone Intravitreal Implant) 0.7 mg Injections for Visual Impairment Due to Diabetic Macular Edema (DME)
Conditions: Diabetic Macular Edema
Sponsor: Allergan

 
NCT03889444 
 
Study ID: CMO-MA-EYE-0564 
 
Title: Drug Utilization Study in Patients Receiving Ozurdex™ (Dexamethasone Intravitreal 
Implant) 0.7 mg Injections for Visual Impairment due to Diabetic Macular Edema (DME) 
 
Protocol Date: 24‐Jul‐2018 

CONFIDENTIAL - Allergan 
 
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Observational Study Protocol 
Study No 
CMO-MA-EYE-0564 
Product 
Dexamethasone intravitreal implant, 0.7 mg (Ozurdex™) 
Study Title 
Drug Utilization Study in Patients Receiving Ozurdex™ 
(Dexamethasone Intravitreal Implant) 0.7 mg Injections 
for Visual Impairment due to Diabetic Macular Edema 
(DME) 
Clinical Phase 
Post-marketing study 
Study Sponsor 
Allergan Pharmaceuticals International Ltd 
Date of Protocol 
24 JULY 2018 
Amendment 
Not applicable 
Version History 
Protocol V1.0  
24 JULY 2018 
 
Marketing authorization holder(s) 
Allergan Pharmaceuticals Ireland 
Castlebar Road, Co. Mayo, Westport 
Ireland 
 
Responsible Parties 
MAH contact person 
 
 
 
 
 
 
  
 
 
 
 
 
A list of study sites, including principal investigators and co-investigators will be available as a 
stand-alone document after the beginning of the study. 
Confidentiality: This protocol is the property of Allergan and may not – in full or in part – be transferred, 
reproduced, published, or otherwise used without the express permission of Allergan. 

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Table of contents 
Approval ........................................................................................................................... 2 
Table of contents .............................................................................................................. 3 
List of Tables .................................................................................................................... 6 
1 
SYNOPSIS ................................................................................................................... 7 
2 
LIST OF ABBREVIATIONS ......................................................................................... 12 
3 
Study Milestones and Timelines ................................................................................ 14 
4 
Amendments and Updates ........................................................................................ 15 
5 
INTRODUCTION ........................................................................................................ 15 
5.1 Background ...................................................................................................... 15 
5.2 Study Rationale ................................................................................................ 17 
6 
OBJECTIVES AND OUTCOME VARIABLES ................................................................... 18 
6.1 Objectives ........................................................................................................ 18 
6.1.1 
Primary objective .................................................................................... 18 
6.1.2 
Secondary objective ................................................................................ 18 
6.2 Outcome Variables ........................................................................................... 18 
7 
STUDY CONDUCT ...................................................................................................... 19 
7.1 Overall Design of the Study .............................................................................. 19 
7.2 Patient Discontinuation, Site Termination or Study Termination ...................... 19 
7.2.1 
Withdrawal of Individual Patients Prior to Study Completion .......................... 19 
7.2.2 
Study or Study Site Termination ............................................................... 19 
7.3 Bias and Limitations of the Study ..................................................................... 19 
7.3.1 
Selection Bias ........................................................................................ 19 
7.3.1.1 
Sites ...................................................................................... 19 
7.3.1.2 
Patients .................................................................................. 20 
7.3.2 
Information Bias ..................................................................................... 20 
7.3.3 
Confounding Bias .................................................................................... 20 
8 
STUDY POPULATION ................................................................................................. 21 
8.1 Sites ................................................................................................................. 21 
8.2 Patients ............................................................................................................ 21 
8.2.1 
Inclusion Criteria .................................................................................... 21 
8.2.2 
Exclusion Criteria .................................................................................... 21 

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8.2.4 
Minimum Required Dataset ...................................................................... 22 
9 
STUDY PROCEDURES ................................................................................................ 23 
9.1 Site Selection, Enrollment and Training ............................................................ 23 
9.1.1 
Sampling ............................................................................................... 23 
9.1.2 
Site Initiation ......................................................................................... 23 
9.1.3 
Site Monitoring ....................................................................................... 23 
9.2 Patient Identification and Selection Procedures ............................................... 24 
10 STUDY ASSESSMENTS ............................................................................................... 25 
10.1 Data Collected in the Screening Log ................................................................. 26 
10.2 Demographics .................................................................................................. 26 
10.3 Medical and Ophthalmic History ....................................................................... 26 
10.4 Prior and Concomitant Treatments ................................................................... 26 
10.4.1 Prior and Concomitant Cataract and Glaucoma Procedures ............................ 26 
10.4.2 Prior and Concomitant Laser Therapy ........................................................ 26 
10.4.3 Prior and Concomitant Other Intravitreal Injections ..................................... 27 
10.4.4 Concomitant Medications ......................................................................... 27 
10.5 Clinical Examinations ....................................................................................... 27 
10.6 Contralateral Eye .............................................................................................. 27 
10.7 Ozurdex Implants ............................................................................................. 27 
10.8 Effectiveness Assessments ............................................................................... 27 
10.8.1 Best Corrected Visual Acuity ..................................................................... 27 
10.8.2 Central Retinal Thickness ......................................................................... 27 
10.9 Safety Assessments .......................................................................................... 28 
10.9.1 Definitions ............................................................................................. 28 
10.9.1.1 Adverse Events ........................................................................ 28 
10.9.1.2 Adverse Reactions .................................................................... 28 
10.9.1.3 Serious Adverse Drug Reactions ................................................. 28 
10.9.1.4 Adverse Events of Special Interest .............................................. 29 
10.9.2 Collection and reporting of Safety Events by Investigators ............................ 29 
10.9.3 Case Processing and Submission to Competent Authorities ........................... 30 
11 DATA SOURCES ......................................................................................................... 30 
12 DATA MANAGEMENT ................................................................................................. 31 

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13 QUALITY CONTROL ................................................................................................... 31 
14 STATISTICAL METHODS ............................................................................................ 32 
14.1 Sample Size ...................................................................................................... 32 
14.2 Study Populations and Analyses ....................................................................... 33 
14.2.1 Study Populations and Analysis Methods .................................................... 33 
14.2.2 Planned Analyses .................................................................................... 34 
14.2.2.1 Disposition and Patients' Characteristics ...................................... 34 
14.2.2.2 Primary Objective .................................................................... 34 
14.2.2.3 Secondary Objectives ............................................................... 34 
14.2.2.3.1 Relationship between Reinjection Intervals and Effectiveness ... 34 
14.2.2.3.2 Reason for Ozurdex Implant Initial Injection and for Reinjection 35 
14.2.2.3.3 Drug Effectiveness in Patients Naïve of any Anti-VEGF Treatment
 ....................................................................................... 35 
14.2.2.3.4 Adverse Events of Special Interest ........................................ 35 
15 ETHICAL CONDUCT OF THE STUDY ............................................................................ 36 
15.1 Ethics Statement .............................................................................................. 36 
15.2 Informed Consent ............................................................................................ 36 
15.3 Institutional Review Board / Independent Ethics Committee Approval ............ 36 
15.4 Data Protection ................................................................................................ 36 
15.5 Adherence to the Protocol ................................................................................ 36 
15.6 Protocol Amendment ........................................................................................ 37 
15.7 Retention of Patient Records ............................................................................ 37 
15.8 Confidentiality .................................................................................................. 37 
16 Plans for dissemintating and communicating study report ....................................... 37 
17 REFERENCES ............................................................................................................. 38 
APPENDICES .................................................................................................................. 40 
 
 

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List of Tables 
Table 1 
Study Milestones and Timelines ............................................................................ 14 
 
 
 
 
Table 4 
Precision and 95% CI of the mean considering a standard deviation ranging from 1.5 to 
3.0, a mean ranging from 4.7 to 6.7 and a sample size of 150 patients ................................... 32 
Table 5 
Precision and 95% CI of the mean considering a mean gain of 11.5 letters, a standard 
deviation ranging from 4.5 to 10.0 and a sample size of 50 patients ........................................ 33 
 
 

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1 
SYNOPSIS 
Title 
Drug Utilization Study in Patients Receiving Ozurdex™ (Dexamethasone 
Intravitreal Implant) 0.7 mg Injections for Visual Impairment due to Diabetic 
Macular Edema (DME) 
 
 
15 JUNE 2018 
Protocol number 
CMO-MA-EYE-0564 
Clinical Trials.gov 
Registration Number 
Not yet registered 
Planned study dates 
Data abstraction is planned to be conducted between third and fourth 
quarters of 2018. 
Objectives 
Primary objective 
The primary objective of this study is to assess reinjection interval of Ozurdex 
implants in patients with DME in real-world in Germany and Switzerland. 
Secondary objectives 
The secondary objectives of this study are: 
• 
To assess relationship between reinjection intervals and effectiveness  
• 
To describe the reasons for reinjection 
• 
To assess drug effectiveness in patients who are naïve of any anti-
vascular endothelial growth factor (VEGF) treatment 
• 
To present those adverse events of special interest (AESIs) that may 
be potentially related to Ozurdex reinjection 
Study Design 
This is a retrospective, non-interventional, observational, multi-center, drug 
utilization study to be conducted in adult patients with visual impairment due 
to DME treated with Ozurdex implants in Germany and Switzerland. The 
design is based on secondary use of data already collected in medical records 
for routine clinical care purpose. 
Rationale 
Drug utilization in real world may not always reflect what has been described 
in clinical trials. Thus, there is a need for data derived from more 
heterogeneous patient populations in real-world healthcare settings, such as 
in observational cohorts, in order to help physicians gain a better 
understanding of the use of Ozurdex. This retrospective study was designed 
to assess the reinjection interval of Ozurdex in routine clinical practice in 
Germany and Switzerland and its relationship with effectiveness and safety of 
the drug. Study outcomes will enhance knowledge of this treatment option. 

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Duration of study 
For each patient, data abstraction will cover at least one year of follow-up 
from date of first Ozurdex implant injection up to 1 September 2018. 
Overall data will be abstracted from 1 January 2015 until 1 September 2018. 
Patient Population and 
Key Selection Criteria 
Male and female patients, aged ≥18 years, who received at least 2 Ozurdex 
implant in the same eye to treat visual impairment due to DME. Among these 
patients, sites will also be requested to do their best to select a subgroup of 
up to 50 patients that are naïve to anti-VEGF treatment prior to first Ozurdex 
implant injection. Patients may contribute at most one eye into the study. If 
both eyes meet the inclusion criteria, the eye that received the most Ozurdex 
injections will be chosen as the study eye. 
Sample Size 
The study aims to select 150 patients. As study primary objective is to assess 
reinjection interval in real-world, sample size calculation were performed to 
evaluate the precision around the mean of the reinjection interval. 
Considering standard deviations ranging from 1.5 to 3, the selection of 150 
patients will enable the description of a mean reinjection interval with 
satisfactory precisions (half of the 95% confidence interval) ranging from 0.2 
to 0.5 months, i.e. from 6 to 15 days (worst case). 
Outcome Variables and 
Assessments 
Ozurdex Real-word Utilization 
• 
Number of Ozurdex implant injections per year 
• 
Time between Ozurdex implants injections 
Effectiveness: 
• 
Best-corrected visual acuity (BCVA) change from time of injection to 
7–12 weeks following each Ozurdex implant injection 
• 
BCVA change from time of first Ozurdex implant injection to 7-12 
weeks following each Ozurdex implant injection 
• 
Central retinal thickness (CRT) by optical coherence tomography 
(OCT) change from time of injection to 7-12 weeks following each 
Ozurdex implant injection 
• 
CRT by OCT change from time of first Ozurdex implant injection to   
7-12 weeks following each Ozurdex implant injection 
Safety: 
• 
Number and percentage of patients who experienced AESIs 
 
 
 
 

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Study Procedures 
Patients' medical charts will be selected over a 4-month period at each site or 
until the study target population has been reached. Site personnel will be 
invited to complete a screening log with all patients who received at least one 
Ozurdex implant injection to help them identify eligible patients.  
For each patient, retrospective data on the study eye will be abstracted from 
existing medical records from time of first Ozurdex implant injection until 1 
September 2018. Data abstraction will cover at least one year of follow-up 
after first Ozurdex injection for all selected patients. The study eye will be 
defined as the eye that received the most Ozurdex injections. Key relevant 
data will also be collected on the contralateral eye. 
Data Collection 
Procedures 
The following data concerning patient treatment and clinical condition will be 
collected at the indicated time points. 
Screening Log 
• 
Ozurdex injected to treat visual impairment due to DME  
• 
Number of Ozurdex implant injection in each eye 
• 
Patient's age at first Ozurdex implant injection 
• 
Date (MM YYYY) of first Ozurdex implant injection 
• 
Date (MM YYYY) of last follow-up visit 
• 
Anti-VEGF injections before first Ozurdex implant injection  
• 
Patient received Ozurdex implants as part or during a clinical study 
• 
Reason why the patient has not been selected for the study, if applicable  
Case Report Form 
Relevant data will be collected at baseline, defined as the period prior to first 
Ozurdex implant injection (index event), and during the study period, defined 
as the period between the first Ozurdex implant injection and 1 September 
2018. 
• 
Demographics at baseline (age and gender) 
• 
Medical and Ophthalmic history (chronic medical conditions and medical 
conditions ongoing at time of first Ozurdex implant injections, glaucoma, 
cataract, and lens status) 
• 
Prior and concomitant treatments in the study eye (prior and concomitant 
cataract and glaucoma procedures, prior and concomitant laser therapy, prior 
and concomitant intravitreal injections other than Ozurdex [including but not 
limited to anti-VEGF injections], concomitant medications) 
• 
Clinical examinations in the study eye (intraocular pressure measurement, 
biomicroscopic and ophthalmomicroscopic exams performed) 
• 
Contralateral eye information (DME status, treatments for DME received 
prior and during the study period)  
• 
BCVA in both eyes at baseline and during the study period 
• 
CRT measured in the study eye at baseline and during the study period  
• 
Ozurdex implant injections in the study eye during the study period(date 
of injections and, if available, reason for initial injection and for reinjections) 
• 
AESIs: glaucoma, intraocular hypertension, hypotony, cataract or lens 

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opacities, ocular bleeding or hemorrhage, retinal detachment, tear or hole, 
vitreous detachment, infection vs. non-infection related ocular inflammation, 
significant vitreous loss, mechanical failure of device and implant 
misplacement, and implant dislocation. 
Note: Only high level information on AESIs has been described above. For additional 
information, please refer to Section 10.9.1.4 in the main body of the protocol. 
Statistical Methods 
Analysis Populations 
Data will be presented for all patients who were selected and met the 
selection criteria. Data will be presented in the subgroup of patients that are 
naïve for anti-VEGF treatment; and if the sample size allows it, analyses will 
also be conducted in a subgroup of patients who received 6 or less anti-VEGF 
treatments prior to the first Ozurdex implant injection. Additional groups also 
may be examined, as deemed appropriate. 
Disposition and Patient's Characteristics 
Disposition of patients in the Analysis Population and number of study and 
contralateral eyes for which data are available will be described. 
Primary Objective 
Number of patients with at least one reinjection and number of reinjections 
per patient during the year following the first Ozurdex implant injection will be 
summarized descriptively for all patients from the Analysis population. For 
patients with more than one year of follow-up, number of patients with at 
least one reinjection and number of reinjections per patient during the follow-
up year considered will be described for each year of follow-up (e.g. 2nd year 
of follow-up, 3rd year of follow-up…). The number and percentage of patients 
receiving each injection (first, second, etc.) will be presented for each year of 
follow-up. 
Time between Ozurdex implant injections will be summarized overall and for 
each reinjection, i.e. first reinjection, second reinjection… 
Secondary Objectives 
Relationship between Reinjection Intervals and Effectiveness  
Analysis will be performed considering each Ozurdex reinjection separately 
(second injection or first reinjection, third injection or second reinjection…). 
Change in BCVA from time of reinjection to 7-12 weeks following reinjection 
and change in BCVA from time of first injection to 7-12 weeks following 
reinjection will be summarized for each reinjection. The same analyses will be 
performed for the change in CRT. 
A first approach to assess the relationship between reinjections intervals and 
effectiveness will be to consider time interval between two injections 
(previous injection - reinjection) as a continuous parameter. The potential 
relationship between time interval and effectiveness will be assessed 
graphically using a scatter plot. Time interval between two injections (in 
months) will be plotted on the horizontal axis and either BCVA change or CRT 
change from time of reinjection to 7-12 weeks following reinjection will be 
plotted on the vertical axis. The corresponding correlation coefficients will be 
calculated. The same scatter plot will be done for the change in BCVA and CRT 
from time of first implant injection to 7-12 weeks following each Ozurdex 

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implant injection. 
A second approach will be to consider time interval between two injections as 
a categorical variable; either 2 categories will be considered according to 
median time interval or other categories will be considered based on observed 
distribution. BCVA change and CRT change from reinjection to 7-12 weeks 
following reinjection and BCVA and CRT change from time of first implant 
injection to 7-12 weeks following each Ozurdex implant injection will be 
described by these categories. 
Reasons for Ozurdex Implant Initial Injection and for Reinjection 
Reason for initial injection and for reinjection of Ozurdex implants will be 
summarized descriptively. 
Drug Effectiveness in Patients Naïve of any Anti-VEGF Treatment 
Change in BCVA from time of reinjection to 7-12 weeks following reinjection 
and change in BCVA from time of first injection to 7-12 weeks following 
reinjection will be summarized for each reinjection considering the subgroup 
of patients who are treatment naïve of any anti-VEGF treatment. The same 
will be performed for the change in CRT. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) potentially related to Ozurdex 
reinjection will be summarized descriptively. Number and percentage of 
patients who experienced AESIs 
 will be 
described overall 
.
 
 
The study shall be conducted in compliance with International Society for Pharmacoepidemiology Good Pharmacoepidemiology Practice (ISPE 
GPP) guidelines , the ethical principles arising from the Declaration of Helsinki revised in 2013, the European Union Good Pharmacovigilance 
practices (GVP), European and National laws in terms of data protection and all current local regulations. Relevant scientific guidelines such as 
ENCePP Guide on Methodological Standards in Pharmacoepidemiology will be considered. 

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2 
LIST OF ABBREVIATIONS 
 
Abbreviation Definition 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AEC 
Additional exclusion criteria 
AESI 
Adverse event(s) of special interest 
BCVA 
Best corrected visual acuity  
CI 
Confidence interval  
CRA 
Clinical research associate(s) 
CRO 
Contract research organization 
CRT 
Central retinal thickness 
DME 
Diabetic macular edema 
EC 
Exclusion criteria 
e-CRF 
Electronic case report form 
EDC 
Electronic data capture 
ENCePP 
European Network of Centres for Pharmacoepidemiology and Pharmacovigilance 
ETDRS 
Early treatment diabetic retinopathy study 
GPP 
Good Pharmacoepidemiology Practice  
GVP 
Good pharmacovigilance practices 
IC 
Inclusion criteria 
ICH 
International conference on harmonization 
ICSR 
Individual case safety report 
IEC 
Independent ethics committee 
IOP 
Intraocular pressure 
ISPE 
International society for pharmacoepidemiology 
MAH 
Marketing authorization holder 
MAR 
Minimum angle of resolution 
MedDRA 
Medical dictionary for regulatory activities 
OCT 
Optical coherence tomography  
OU 
Oculus uterque 
SADR 
Serious adverse drug reaction 

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SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Study eye 
SUSAR 
Suspected unexpected serious adverse reactions  
VEGF 
Vascular endothelial growth factor 
WHO 
World Health Organization 
 

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3 
STUDY MILESTONES AND TIMELINES 
The planned study milestones and timelines are described in Table 1 below. 
Table 1 
Study Milestones and Timelines 
Milestone 
Estimated Date 
Ethics submission 
Third quarter 2018 
Start of data collection[a] 
Third quarter 2018 
End of data collection[b] 
Fourth quarter 2018 
Final Report of study results 
Second quarter 2019 
[a] Date of start of data collection will be considered as the first patient entered in the eCRF 
[b] Date of end of data collection will be considered as date of database lock. 
 

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4 
AMENDMENTS AND UPDATES 
This section is not applicable (original protocol). 
5 
INTRODUCTION 
5.1 
Background 
Ozurdex® is a biodegradable solid polymer drug delivery system containing 0.7 mg of 
dexamethasone. A single-use applicator with a 22-gauge needle that leaves a sutureless self-
sealing wound is used to place the dexamethasone implant into the vitreous cavity. The sustained-
release formulation was designed to release dexamethasone from the implant for up to 6 months. 
Ozurdex was granted a marketing authorization in the European Union in 2010 for the treatment of 
adult patients with macular edema following vein occlusion. In 2011, Ozurdex was furthermore 
approved for treatment of adult patients with inflammation of the posterior segment of the eye 
presenting as non-infectious uveitis. More recently, in 2014, Ozurdex was approved for treatment 
of adult patients with visual impairment due to diabetic macular edema (DME) who are 
pseudophakic or who are considered insufficiently responsive to, or unsuitable for non-
corticosteroid therapy1. 
DME is a common manifestation of diabetic retinopathy; diabetic retinopathy being microvascular 
abnormalities seen in the fundus of persons with diabetes. In most studies, DME is defined by hard 
exudates in the presence of microaneurysms and blot hemorrhages, resulting in increased central 
retinal thickness (CRT) within one disc diameter of the foveal center. Clinically significant macular 
edema is the most severe spectrum of DME, and was defined by the presence of edema within 
500 μm of the foveal center, or focal photocoagulation scars present in the macular area. The 
prevalence of DME in population-based studies among type-1 diabetes patients varied between 
4.2% and 7.9%2. In patients with type-2 diabetes it was between 1.4% and 12.8%. DME is a 
leading cause of serious central visual loss impairment in diabetic patients. Due to worldwide rise of 
diabetes mellitus and of life expectancy of those with diabetes mellitus, burden of illness of 
microvascular complications, such as DME, is expected to increase over time. 
Clinical evaluation of DME may be difficult and subjective. Gold standard for DME diagnostic still 
remains the fluorescein angiography, but optical coherence tomography (OCT) can be used for 
screening, classification, monitoring, and treatment evaluation of the DME. It has the ability to 
provide information on CRT as well as distinct morphological features of the edema. 
The chance of spontaneous improvement in the best-corrected visual acuity (BCVA) and decrease 
in CRT is limited, so the prognosis of DME without appropriate treatment is generally disappointing. 
Several therapeutic options are available. Focal and grid laser photocoagulation has represented 
the standard of care for treatment of DME prior to the introduction of intravitreal approach, i.e. 
anti-vascular endothelial growth factor (anti-VEGF) and corticosteroids. Approved anti-VEGF 
therapies include ranibizumab (Lucentis®, Novartis) and aflibercept (Eylea®, Bayer HealthCare). 
Even though not currently approved, bevacizumab (Avastin®, Genetech/Roche) is also used off-
label for the treatment of retinal diseases, including DME3,4. Anti-VEGF agents restore vision in a 
substantial proportion of treated patients5,6. However, drawbacks have been identified for anti-
VEGF patients: patients treated with anti-VEGF may be at increased risk to develop systemic 
(thromboembolic) adverse events (AEs) compared with sham/laser treatment arms7; treatment 

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with anti-VEGF require monthly injections at the clinic for an extended period of time; and some 
patients are partial or non-responders to anti-VEGF treatments8,9. Corticosteroids therapy, through 
anti-inflammatory properties, and VEGF inhibition, inhibit many of the inflammatory processes 
known to be involved in the progression of DME. Commercially available corticosteroids compounds 
for intravitreal use include fluocinolone (Iluvien®, Alimera Sciences) and Ozurdex®. Even though 
not approved for this indication, triamcinolone acetonide is also used off-label for the treatment of 
DME. Long-acting corticosteroid implants such as Iluvien and Ozurdex have the benefit of reducing 
the number and frequency of injections10,11. In the European Society of Retina Specialists 
(EURETINA) guidelines for the management of DME, the importance of corticosteroids in the 
armamentarium of drugs for treating DME patients is recognized; however corticosteroids are 
recommended to be administered in non-responders who have already been treated with anti-
VEGF. First line therapy with Ozurdex should be considered in patients with history of major 
cardiovascular events and in patients that are not willing to come for monthly injections in the first 
6 months of therapy5. 
Ozurdex efficacy in patients with visual impairment due to DME was assessed in 2 randomized, 
multi-center, masked, sham-controlled, phase III trials, the MEADs trials, over a 3-year period12. 
At study end, 22.2% of patients who received Ozurdex (N=351) had a ≥15-letter improvement 
compared to 12.0% in the sham group (N=350) (p<0.001). Mean BCVA average change over the 
3-year period was higher in patients treated with Ozurdex (3.5 letters) than in the sham group (2.0 
letters) (p=0.023). Mean average reduction in CRT from baseline was greater with Ozurdex 0.7 mg 
(-111.6 µm) than with sham (-41.9 µm). In a prospective, multi-center, open-label, 1-year follow-
up study, the CHAMPLAIN trial, 27 treatment-naïve patients with type-2 diabetes and affected by 
DME were treated with Ozurdex13. During the one-year follow-up period, most patients (66%) 
received a second Ozurdex injection with a mean time between injections of 6.7±2.3 months. One 
month after the first injection BCVA significantly improved compared to baseline (-0.02 LogMAR) 
and CRT significantly decreased (-79 µm).  
In the MEADs trials, the most commonly reported AEs following treatment with Ozurdex are those 
frequently observed with ophthalmic steroid treatment or intravitreal injections: cataract formation, 
elevated intra-ocular pressure (IOP), and conjunctival or vitreal hemorrhage12. In these trials, 
cataract-related AEs were observed in 67.9% of patients with a phakic eye at baseline compared to 
20.4% of patients in the sham group. The incidence of cataract-related AEs increased after the first 
year after Ozurdex injection. Approximately one-third of patients with Ozurdex implant had a 
clinically significant increase in IOP requiring treatment during the study. Vitreous hemorrhage 
considered possibly related to treatment was reported in 3.5% of patients with Ozurdex implant 
compared to 0.0% in the sham group. Less frequently reported but more serious adverse drug 
reactions include endophthalmitis, necrotizing retinitis, retinal detachment and retinal tear. With 
the exception of headache and migraine, no systemic adverse drug reactions were identified with 
the use of Ozurdex. Finally, several adverse drug reactions, such as conjunctival hemorrhage, 
visual acuity reduced, vitreous detachment, vitreous floaters, vitreous opacities, eye pain, 
photopsia, conjunctival edema, conjunctival hyperemia, endophthalmitis, retinal detachment, 
retinal tear, hypotony of the eye, anterior chamber inflammation, anterior chamber cells/flares, 
abnormal sensation in eye, sclaral hyperemia, device dislocation, and complication of device 
insertion, have been identified in Ozurdex SmPC as related to the intravitreal injection procedure1, 
i.e. the frequency of these AEs is proportional to the number of treatments given. 
 

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5.2 
Study Rationale 
Ozurdex efficacy and safety have previously been shown in PLACID, MEAD and CHAMPLAIN clinical 
trials. While large phase 3 clinical trials are fundamental to supporting the registration of new 
drugs, these studies were performed in highly selected patients under well controlled conditions. In 
MEADs clinical trials, patients were eligible for retreatment if it had been at least 6 months since 
the previous study treatment. Drug utilization in real world may not always reflect what has been 
described in clinical trials. Thus, there is a need for data derived from more heterogeneous patient 
populations in real-world healthcare settings, such as in observational cohorts, in order to help 
physicians gain a better understanding of the use of Ozurdex. This retrospective study was 
designed to assess the reinjection interval of Ozurdex in routine clinical practice in Germany and 
Switzerland and its relationship with effectiveness and safety of the drug. Study outcomes will 
enhance knowledge of this treatment option. 

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6 
OBJECTIVES AND OUTCOME VARIABLES 
The study objectives were not based on any hypothesis. 
6.1 
Objectives 
6.1.1 Primary objective 
The primary objective of this study is to assess reinjection interval of Ozurdex implants in patients 
with DME in real-world in Germany and Switzerland. 
6.1.2 Secondary objective 
The secondary objectives of this study are: 
• 
To assess the relationship between reinjection intervals and drug effectiveness 
• 
To describe the reasons for reinjection 
• 
To assess drug effectiveness in patients who are naïve of any anti-VEGF treatment 
• 
To present those adverse events of special interest (AESIs) that may be potentially related 
to Ozurdex reinjection 
6.2 
Outcome Variables 
Ozurdex Real-word Utilization 
• 
Number of Ozurdex implant injections per year 
• 
Time between Ozurdex implants injections 
Effectiveness: 
• 
BCVA change from time of injection to 7–12 weeks following each Ozurdex implant 
injection 
• 
BCVA change from time of first Ozurdex implant injection to 7-12 weeks following each 
Ozurdex implant injection 
• 
CRT by OCT change from time of injection to 7-12 weeks following each Ozurdex implant 
injection 
• 
CRT by OCT change from time of first Ozurdex implant injection to 7-12 weeks following 
each Ozurdex implant injection 
Safety: 
• 
Number and percentage of patients who experienced AESIs 
 
 
 
 

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7 
STUDY CONDUCT 
7.1 
Overall Design of the Study 
This is a retrospective, non-interventional, observational, multi-center, drug utilization study to be 
conducted in adult patients with visual impairment due to DME treated with Ozurdex implants in 
Germany and Switzerland from 1 January 2015 to 1 September 2018. Data from approximately 
150 patients will be collected by retrospective review of medical charts; including up to 50 patients 
that are naïve of any anti-VEGF treatment before their first Ozurdex implant injection. Sites will be 
hospital-based experienced medical retina centers treating DME patients. 
Patients' medical charts will be selected over a 4-month period at each site or until the study target 
population has been reached. Site personnel will be invited to complete a screening log with all 
patients who received at least one Ozurdex implant injection after the 1 January 2015 to help them 
identify eligible patients. For each patient, retrospective data on the study eye will be abstracted 
from existing medical records from time of first Ozurdex implant injection until 1 September 2018. 
Data abstraction will cover at least one year of follow-up after first Ozurdex injection for all 
selected patients. The study eye will be defined as the eye that received the most Ozurdex 
injections. Key relevant data will also be collected on the contralateral eye. 
Study procedures, and evaluations are described in detail in Sections 9 to 11 and data to be 
collected are summarized in Table 2. Safety events to be collected are described in Section 10.9. 
7.2 
Patient Discontinuation, Site Termination or Study 
Termination 
7.2.1 Withdrawal of Individual Patients Prior to Study Completion 
Considering the retrospective study design, no withdrawal of individual patients prior to study 
termination is expected. 
7.2.2 Study or Study Site Termination 
The Sponsor reserves the right, at any time, to discontinue selection of additional patients into the 
study, at any site; or to discontinue the study for administrative reasons. 
7.3 
Bias and Limitations of the Study 
7.3.1 Selection Bias 
7.3.1.1 Sites 
Sites will be selected from hospital-based experienced medical retina centers treating DME patients 
as these centers will be experienced in intravitreal Ozurdex injections. Because the participating 
sites comprise a population of volunteers, a non-response selection bias is possible. 

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7.3.1.2 Patients 
In order to limit bias in the selection of patients, sites will attempt to consecutively select all 
patients who meet the selection criteria, regardless of demography or other considerations, based 
on date of first Ozurdex implant injection. All patients meeting the selection criteria, regardless of 
their selection for the study, will be identifiable in a screening log collecting minimum non-
identifying patient information (see Sections 9.2 and 10.1). Characteristics of selected and non-
selected patients will be compared to assess patient selection bias and reason for not being 
selected will be described (patient did not met selection criteria, lack of time, quotas were met, 
etc.). 
7.3.2 Information Bias 
Information bias is a distortion in the estimate of association between risk factor and disease that 
is due to systematic measurement error or misclassification of patients on one or more variables, 
either risk factor or disease status. As the study is retrospective, the study will rely on data that 
have already been collected for another purpose (e.g. patient care). As a result, not all data to be 
collected in this study may be recorded in the medical charts, leading to a potential bias due to 
missing data. Moreover, as the study is anonymous, no queries will be issued to the sites in case of 
missing or incoherent data. Finally, as this is a multicenter study, the methods used to estimate 
the data variables collected during the chart review process may be heterogeneous across sites. 
This could potentially introduce a systematic bias into the results and would likely result in greater 
variability in the study result (e.g. OCT method used to measure CRT or method used to measure 
BCVA). 
Information bias can be minimized by the use of electronic data capture technology. In addition to 
minimize the burden on the investigators and the sites, electronic data capture technology will 
maximize the quality and relevance of the data using automated online controls (e.g., automated 
controls on value ranges, units, internal consistency, and missing key data). To complement 
automated online controls, principal investigators will be requested to review all entered data 
submitted in the electronic data capture system. 
7.3.3 Confounding Bias 
Confounding bias may result from selective prescribing of a particular treatment to more severely 
affected patients. As a result of a higher background risk, reported event rate may be higher and 
give the appearance of an elevated risk related to the use of the treatment. The collection of 
relevant medical information prior to first Ozurdex implant injection will help to identify the 
presence of elevated background risk of safety events, so that incidence of safety events can be 
compared through subgroup analysis to what was observed in available literature to determine 
whether the elevated risk is likely to be related to background risk or use of Ozurdex (e.g. previous 
occurrence of glaucoma, previous cataract, previous anti-VEGF treatment). 

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8 
STUDY POPULATION 
8.1 
Sites 
Site selection will aim to recruit qualified ophthalmologists experienced in intravitreal injections 
who are most likely to treat patients with DME with Ozurdex. A sample of ophthalmologists working 
in experienced medical retinal centers treating DME patients will thereby be selected. 
8.2 
Patients 
From a public health and market access perspective, the present study population constitutes a 
broader real-world patient population than that reflected in clinical trials. The present study design 
cannot make any conclusions on causal relationships, but can rather explore real-world Ozurdex 
drug utilization patterns, effectiveness and safety. It is expected that the results from this study 
may be generalizable to the overall population presenting with DME and treated with Ozurdex in 
Germany and Switzerland. 
Patients may contribute at most one eye into the study. If both eyes meet the inclusion criteria, the 
eye that received the most Ozurdex injections will be chosen as the study eye. 
8.2.1 Inclusion Criteria 
A patient must meet all of the following criteria to be eligible for participation in the study. 
1. 
Patient received at least two Ozurdex implants in the study eye to treat visual 
impairment due to DME 
2. 
Male or female patient aged ≥18 years at time of first Ozurdex implant injection 
3. 
First Ozurdex implant injection occurred after 1 January 2015 
4. 
Patient was followed-up at the site for at least 12 months after the first Ozurdex implant 
in the study eye 
8.2.2 Exclusion Criteria 
A patient who meets the following criteria is not eligible for participation in the study. 
1. 
Patient received Ozurdex implants as part or during a clinical study 
 
 
 
 
  
 
 

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8.2.4 
Minimum Required Dataset 
Ozurdex Real-word Utilization (in study eye) 
• 
Number of Ozurdex implant injections 
• 
Date of Ozurdex implant injections 
• 
BCVA prior to injection time and following each Ozurdex implant 
• 
Receipt of concomitant DME treatment in the study eye 
Patient characteristics 
• 
Age 
• 
Gender 
• 
Date of DME diagnosis in the study eye 
Other treatment 
• 
Prior and concomitant other intravitreal injections (if relevant) 

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9 
STUDY PROCEDURES 
9.1 
Site Selection, Enrollment and Training 
9.1.1 Sampling 
Allergan will identify sites among experienced medical retina centers treating DME patients. Sites 
will be identified using Allergan field-based knowledge.  
The study will be proposed to all the sites identified by Allergan; a recruitment mail containing the 
study summary, the site qualification questionnaire and a reply coupon will be sent to all these 
sites. If the return rate is insufficient, non-responders will be contacted by telephone to fill out the 
site qualification questionnaire. 
The Sponsor or designee will qualify sites with sufficient resources (time, personnel, and facilities) 
to participate in the study. Sites will be required to obtain approval from the appropriate 
Independent Ethics Committee (IEC), and will be responsible for maintaining all related documents, 
before enrollment of any patient into the study. 
Recruitment will end as soon as approximately 10 sites, 7 in Germany and 3 in Switzerland, are 
qualified to participate in the study. 
9.1.2 Site Initiation 
Sites will receive a study kit once all the necessary administrative procedures have been completed 
(confidentiality agreement, research contract agreement, curriculum vitae… where applicable). 
The study kit contains the study protocol and the e-CRF user manual. On reception of the study kit, 
an initiation telephone call will be organized by Clinical Research Associates (CRA) to explain the 
protocol, data collection, and the practical aspects of the study. 
In addition, designated study personnel will participate in a training program that will encourage 
consistency of process and procedures at the investigative sites and ensure collection of high-
quality data for this study. All sites will be trained on the protocol, study logistics, data protection, 
and the electronic data capture (EDC) system. Retraining will be conducted as needed. 
9.1.3 Site Monitoring 
During the chart-extraction period, sites will be contacted by telephone by CRAs to follow the site 
identification of patients, the e-CRF completion and to answer any questions sites may have 
concerning data to be collected and the logistics of the study. Frequency of telephone calls will be 
site dependent and based on identified needs for each site. A close out call will be performed by 
CRAs at the end of the study. Site monitoring processes will be further detailed in the Site 
Management and Monitoring Plan. 

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9.2 
Patient Identification and Selection Procedures 
Medical charts will be screened by the investigative site personnel to identify patients who satisfy 
all the inclusion and none of the exclusion criteria. Once a site has been initiated, site personnel 
will be invited to complete a screening log with all patients who received their first Ozurdex implant 
injection from 1 January 2015 until 1 September 20171. Data collected in the screening log, listed 
in Section 10.1, will help site personnel identify eligible patients. Screening logs will be anonymized 
before being entered in the study database. 
Non-competitive selection of eligible patients 
Upon screening log completion, the sites will proceed through the patients listed in the screening 
log and will select all consecutive patients who meet the inclusion criteria (Section 8.2.1) and none 
of the exclusion criteria (Section 8.2.2), starting with patients who received their first Ozurdex 
injection the closest to 1 January 2015. Patient selection will not be competitive between countries 
and will stop when the quotas of eligible patients has been reached in each country, i.e. 
approximately 70 patients in Germany and 30 patients in Switzerland. Consent from patients will 
not be requested; as the study is retrospective and anonymized, a waiver of consent will have been 
requested from the Ethics Committees. 
Competitive selection of patients - patients who are naïve to anti-VEGF treatment 
During the patient selection process, special attention will be given to patients that are naïve to 
anti-VEGF treatment prior to first Ozurdex implant injection 
 
, and sites will be asked to do their best to select a 
predetermined number of patients who do not meet this exclusion criteria. Recruitment of patients 
that are naïve to anti-VEGF treatment will stop when approximately 50 patients have been selected 
in Germany and Switzerland.  
Overall, patient selection will stop when 150 patients have been selected for the study. The number 
of patients included at each site, in particular the number of patients that are naïve to anti-VEGF 
treatment, will be chosen based on feasibility surveys and consultations with the Sponsor. 
                                          
1 1 September 2017 was chosen to get at least 1 year of follow-up data on 1 September 2018 for all selected patients. 

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10 
STUDY ASSESSMENTS 
This is a retrospective, observational study and patient data collected from the sites will be 
abstracted from medical charts. Baseline will be defined as the period prior to first Ozurdex implant 
injection (index event) and study period will be defined as the period between the first Ozurdex 
implant injection and 1 September 2018. 

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10.1 
Data Collected in the Screening Log 
Once a site has been initiated, site personnel will be invited to complete a screening log with all 
patients who received at least one Ozurdex implant injection.
 
 
10.2 
Demographics 
Patients' age at first Ozurdex implant injection and gender will be recorded in the eCRF. 
10.3 
Medical and Ophthalmic History 
Chronic medical conditions and medical conditions ongoing at time of first Ozurdex implant 
injection will be collected, along with year of onset. History of glaucoma, cataract and lens status 
(phakic or pseudophakic) will be collected. 
DME history, i.e. date of onset of symptoms and date of DME diagnosis in the study eye, will be 
collected. 
10.4 
Prior and Concomitant Treatments 
10.4.1 Prior and Concomitant Cataract and Glaucoma Procedures 
Cataract and glaucoma procedure performed on the study eye prior to the study period and during 
the study period will be recorded (e.g., cataract surgery, glaucoma laser, trabeculectomy, 
glaucoma valve implant, laser peripheral iridotomy, other procedures). 
10.4.2 Prior and Concomitant Laser Therapy 
Focal/grid laser treatments for DME occurred on the study eye prior to the study period and during 
the study period will be recorded (date of treatment, focal or grid laser photocoagulation). 

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10.4.3 Prior and Concomitant Other Intravitreal Injections 
Intravitreal injections other than Ozurdex received prior to study period will be recorded for the 
study eye: name, number of treatments, and last treatment date. 
At each visit occurred during the study period, intravitreal injections other than Ozurdex received in 
the study eye will be recorded. 
Special focus will be placed on the following intravitreal injections: 
• 
Anti-VEGF therapies such as Lucentis®, Eylea®, and Avastin® 
• 
Corticosteroid therapies other than Ozurdex such as Iluvien® and triamcinolone 
10.4.4 Concomitant Medications 
A pre-defined list of concomitant medications that may have an impact on short term efficacy and 
safety of the drug received at time of first Ozurdex implant administration and during the study 
period will be recorded (inclusive of IOP medications, corticoid medications, non-steroid anti-
inflammatory drug, immunosuppressive drug, and antithrombotic agents) : medication name, start 
date, end date, indication (eye condition vs. other medical condition). 
10.5 
Clinical Examinations 
Biomicroscopic and ophthalmomicroscopic exams performed in the study eye (yes/no), and 
intraocular pressure value measured in the study eye will be collected at baseline and at each visit 
occurred during the study period. 
10.6 
Contralateral Eye 
DME status in the contralateral eye will be recorded at baseline and at all visits occurred during the 
study period. 
Treatments for DME received prior to study period will be recorded for the contralateral eye. For 
each visit occurred during the study period, treatments received in the contralateral eye (inclusive 
of intravitreal treatment) will be recorded. 
10.7 
Ozurdex Implants 
For each Ozurdex implant injection performed in the study eye, date of injection will be recorded. If 
available, reason for initial injection and reinjections will be collected. 
10.8 
Effectiveness Assessments 
10.8.1 Best Corrected Visual Acuity 
BCVA will be collected at baseline and at all visits during the study period in both study and 
contralateral eyes. Values will be recorded in the eCRF according to local practice (Snellen, MAR, 
EDTRS, etc.) along with scale name or method used to assess BCVA. 
10.8.2 Central Retinal Thickness 
CRT measured in the study eye will be collected at baseline and at all visits during the study period 
if it was measured using OCT. Technology and device brand used to measure OCT will also be 
collected. 

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10.9 
Safety Assessments 
10.9.1 Definitions 
10.9.1.1 Adverse Events 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical trial 
subject administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not the event is considered causally related to the use of this 
medicinal product (see GVP Annex IV, ICH-E2D guideline14). 
10.9.1.2 Adverse Reactions 
An adverse reaction is a response to a medicinal product which is noxious and unintended 
[DIR2001/83/EC Art 1(11)] (see GVP Annex I, Definitions15). Synonyms are adverse drug reactions 
(ADR), suspected adverse (drug) reaction, adverse effect, and undesirable effect. Response in this 
context means that causal relationship between the medical product and an AE is at least a 
reasonable possibility (see Annex IV, ICH-E2A Guideline 516). Adverse reactions may arise from use 
of the product within or outside the terms of the marketing authorization or from occupational 
exposure. Conditions of use outside the marketing authorization include off-label use, overdose, 
misuse, abuse and medication errors. 
For regulatory reporting purposes on post approval safety data, if an AE is spontaneously reported, 
even if the relationship is unknown or unstated, it meets the definition of an ADR. 
10.9.1.3 Serious Adverse Drug Reactions  
An SADR is an ADR that meets any of the following criteria (see GVP Annex IV, ICH-E2A Guideline 
516): 
• 
Results in Death of patient. 
• 
Is life-threatening: this refers to an event/reaction in which the patient was at risk of 
death at the time of the event/reaction; it does not refer to an event/reaction which 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization: An event/reaction that results in an admission to the 
hospital for any length of time. This does not include an emergency room visit or admission 
to an outpatient facility. 
• 
Results in prolongation of existing hospitalization: An event/reaction that occurs while 
the study patient is hospitalized and prolongs the patient's hospital stay. 
• 
Is a congenital anomaly/birth defect: An anomaly detected at or after birth, or any 
anomaly that results in fetal loss. 
• 
Results in persistent or significant disability/incapacity: An event/reaction that results 
in a condition that substantially interferes with the activities of daily living of a study 
patient. Disability is not intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle). 

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• 
Is a medically important event or reaction: An important medical event/reaction that 
may not be immediately life-threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the patient and may require medical or surgical 
intervention to prevent any of the outcomes listed above (i.e., death of patient, life-
threatening, hospitalization, prolongation of hospitalization, congenital anomaly/birth defect, 
or persistent or significant disability/incapacity). Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. 
• 
Any suspected transmission via a medicinal product of an infectious agent is also 
considered as a SADR 
10.9.1.4 Adverse Events of Special Interest 
An AE of special interest (AESI) (serious or non-serious) is an AE specific to the sponsor’s product 
or program. Such an event might warrant further investigation to characterize and understand it. 
10.9.2 Collection and reporting of Safety Events by Investigators 
The study will be conducted in accordance with Directive 2001/83/EC, Regulation (EC) No 
726/2004, Commission Implementing Regulation (EU) No 520/2012 as amended and detailed in 
GVP Modules VI17. 
Considering that study aims to explore the potential impact of recurrent Ozurdex injections, and 
not confirm the whole safety profile, and considering the current knowledge of the study drug 
safety profile, this study focuses only on the following AESIs (related or not to Ozurdex): 
• 
Glaucoma, defined as damage to the optic nerve with progressive vision loss (open angle 
glaucoma, normal tension glaucoma, and acute angle closure glaucoma) 
• 
Intraocular hypertension, defined as IOP without meeting the criteria for glaucoma 
• 
Hypotony, defined as low IOP ≤5 mmHg 
• 
Cataract or lens opacities (nuclear sclerotic, cortical and posterior subcapsular) 
• 
Ocular bleeding or hemorrhage (conjunctival, anterior chamber, vitreous, macular, 
retinal) 
• 
Retinal detachment, tear or hole 
• 
Vitreous detachment 
• 
Infection vs. Non-infection related Ocular inflammation (conjunctivitis, blepharitis, 
episcleritis, scleritis, keratitis, uveitis, retinitis and endophtalmitis)  
• 
Significant vitreous loss 
• 
Mechanical failure of device and implant misplacement 
• 
Implant dislocation 
In addition to AESIs, off-label use should be collected, and reported to Allergan whether or not off-
label use was associated with an AE. 
Due to the retrospective design of the study, the reporting of safety events to the sponsor is not 
solicited for this study. However, investigators are reminded about the possibility for them to report 

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any suspected ADRs directly to the marketing authorization holder of the suspected medicinal 
product (studied or not) or to the concerned competent authority via the national spontaneous 
reporting system. 
10.9.3 Case Processing and Submission to Competent Authorities 
In accordance with GVP Module VI.C.1.2.1.217 (non-interventional post-authorization studies with a 
design based on secondary use of data) the submission of suspected ADRs in the form of individual 
case safety reports (ICSRs) is not required. Therefore, Allergan will not submit any ICSRs for 
solicited ADRs collected for the study. However, all AEs/ADRs collected for the study will be 
recorded in the study database and summarized in study reports. 
The investigators are responsible for maintaining compliance with any applicable site-specific 
requirements related to the reporting of SAEs or other safety information to the local IEC that 
approved the study. 
11 
DATA SOURCES 
This is a retrospective, observational study, and patient data collected from the sites will be 
abstracted from medical charts. 

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12 
DATA MANAGEMENT 
All data collected in the context of this study will be stored and evaluated in accordance with 
regulatory requirements and applicable guidance for electronic records. 
Electronic data collection will be performed using an e-CRF. Investigators or study personnel will 
enter data into the electronic data capture (EDC) system according to the schedule of assessments 
(Table 2) and according to instructions from the Sponsor and/or designee. Only authorized 
personnel will have access to the EDC system. Data will be anonymized and once entered in the 
system, investigators and study personnel will not be able to identify patients. 
Each investigator is responsible for ensuring that accurate data are entered into the EDC system in 
a timely manner. Specific processes used to manage the data throughout the study will be 
documented in the Data Management Plan. Briefly, on-line logic checks will be built into the 
system, so that missing or illogical data are not submitted. In the event that inconsistent data 
persist, no queries will be issued as investigators will not be able to connect the patient with 
his/her identification number. Consequently, to prevent as much as possible remaining inconsistent 
data, all data entered into the eCRF should be reviewed by the principal investigator. The principal 
investigator will be responsible for endorsing data within the eCRF. This approval method will 
include applying an electronic signature, a uniquely assigned user name, and a password that 
together will represent a traditional handwritten signature. 
Medical history, concomitant disease, and AEs will be coded, using Medical Dictionary for 
Regulatory Activities (MedDRA, the most recent version). Drugs will be coded with the WHO Drug 
Dictionary. 
A final validation of the database will be performed, and the database will be locked, before the 
statistical analysis is conducted. 
13 
QUALITY CONTROL 
Designated study personnel will participate in a training program that will encourage consistency of 
process and procedures at the investigative site and ensure collection of high-quality data for this 
study. All sites will be trained on the protocol, study logistics, and the EDC system. Retraining will 
be conducted as needed. 
The Sponsor and its representatives will monitor the study over the telephone on a regular basis, 
according to the Monitoring Plan. At the monitoring visits, the progress of the study and any 
procedural or data issues will be discussed with the site and/or designee (see Section 9.1.3). 
Quality controls performed during statistical analyses will be described in the statistical analysis 
plan (SAP). 
Secure electronic archive will be maintained and will include but will not be limited to: final raw 
data, analysis datasets, programs and associated documentation. Access to the archive will be 
controlled and limited to authorized personnel only. 

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14 
STATISTICAL METHODS 
14.1 
Sample Size 
The study aims to select 150 patients. As study primary objective is to assess reinjection interval of 
Ozurdex implant in real-world, sample size calculations were performed to evaluate the precision 
around the mean of the reinjection interval. 
Few data were published on the reinjection interval in patients diagnosed with diabetic macular 
edema in real-world. Matropasqua et al.13 reported a mean ± standard deviation (SD) of 6.7±2.3 
months in 27 Italian patients. Querques et al.18 reported a mean of 4.9 and 4.7 months from 
respectively 570 French patients of a pharmacist database and 114 patients from the French Social 
Security database (no standard deviations were available). The same study also reported a mean 
(±SD) of 4.8±1.82 months between reinjections based on data from 111 French ophthalmologists 
who completed a survey about their practice. 
The precision of the 95% confidence interval (CI) of the mean (ω, half of the width of the CI) is 
determined using the following formula: 
n
SD
96
.
1
×
=
ω
, where SD is the standard deviation and n is the sample size. 
Table 4 shows the precision and 95% CI of the mean considering a SD ranging from 1.5 to 3.0 and 
a sample size of 150 patients. 
 
Table 4 
Precision and 95% CI of the mean considering a standard deviation ranging from 1.5 to 
3.0, a mean ranging from 4.7 to 6.7 and a sample size of 150 patients 
SD 
Mean (month) 
 
ω 
4.7 
5.5 
6.0 
6.7 
1.5 
0.2 
4.5-4.9 
5.3-5.7 
5.8-6.2 
6.5-6.9 
2.0 
0.3 
4.4-5.0 
5.2-5.8 
5.7-6.3 
6.4-7.0 
2.5 
0.4 
4.3-5.1 
5.1-5.9 
5.6-6.4 
6.3-7.1 
3.0 
0.5 
4.2-5.2 
5.0-6.0 
5.5-6.5 
6.2-7.2 
 
Considering SD of the mean reinjection interval ranging from 1.5 to 3 months, the selection of 150 
patients will enable the description of a mean reinjection interval with precision ranging from 0.2 to 
0.5 months, i.e. 6 to 15 days (worst case). 
For example, for a mean interval between two Ozurdex injections of 6.0 months, the 95% CI of the 
mean would be 6.0 [5.5-6.5] months in the worst case (i.e., 183 days [168-198], ω =15 days). 
 
                                          
2 Standard deviation was not clearly available in the paper and was recalculated from available data. 

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A secondary objective of the study is to assess drug effectiveness in a subgroup of patients who 
are naïve of any anti-VEGF treatment. One of the outcomes of interest for this subgroup of patients 
will be the change in BCVA from the first injection to 7-12 weeks following each reinjection. 
In 2015 Escobar-Barranco et al 19 reported a difference in visual actuity from baseline to 6 months 
(mean ± SD) of 11.5±4.6 ETDRS letters in 36 treatment naïve patients whereas in 2018 Iglicki et 
al.20 reported a gain at 24 months (mean ± SD) of 11.3±10.0 letters in 71 eyes of treatment naïve 
patients. 
The precision and 95% CI of the mean have been calculated considering a mean gain of 11.5 
letters, standard deviation ranging from 4.5 to 10.0 and a sample size of 50 patients (Table 5). 
 
Table 5 
Precision and 95% CI of the mean considering a mean gain of 11.5 letters, a 
standard deviation ranging from 4.5 to 10.0 and a sample size of 50 patients 
SD 
ω 
95% CI 
4.5 
1.3 
10.2-12.8 
6.0 
1.7 
9.8-13.2 
8.0 
2.2 
9.3-13.7 
10.0 
2.8 
8.7-14.3 
 
Considering SD ranging from 4.5 to 10.0, a subgroup of 50 patients who are treatment naïve will 
enable to describe a mean change in visual acuity with precision ranging from 1.3 to 2.8. For 
example, for a mean change in visual acuity of 11.5, the 95%CI of the mean will be 11.5 [8.7-
14.3] letters in the worst case. It has been considered as satisfactory for this secondary objective. 
14.2 
Study Populations and Analyses 
A formal SAP that will provide details of all analyses and presentation of study data will be 
approved prior to data analysis. Statistical analysis will be carried out using SAS software version 
9.2 or later. 
14.2.1 
Study Populations and Analysis Methods 
• 
Analysis Population: data will be summarized for all patients who were selected and met 
the selection criteria. 
• 
Subgroups analysis will be conducted in patients who are naïve for anti-VEGF treatment. 
If the sample size allows it, analyses will also be conducted in a subgroup of patients 
who received 6 or less anti-VEGF treatments prior to the first Ozurdex implant injection. 
• 
Additional groups also may be examined, as deemed appropriate such as according to 
lens status at baseline (phakic vs. pseudophakic) or according to concomitant 
treatments (concomitant anti-VEGFs vs. Ozurdex only). 
Continuous variables will be described by their mean, SD, median, first and third quartiles, extreme 
values (minimum and maximum) and the number of missing data. 
Categorical variables will be described by the total and percentage of each response and the 
number of missing data. 

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Two-sided 95% CI of the mean and of percentage may also be calculated when appropriate. Data 
may also be presented graphically when relevant. 
14.2.2 Planned Analyses 
14.2.2.1 Disposition and Patients' Characteristics 
Disposition of patients in the Analysis Population and number of study and contralateral eyes for 
which data are available will be described. 
Clinical examinations, prior and concomitant treatments, and contralateral eye data will be 
summarized descriptively. 
14.2.2.2 Primary Objective 
Number of patients with at least one reinjection and number of reinjections per patient during the 
year following the first Ozurdex implant injection will be summarized descriptively for all patients 
from the Analysis population. For patients with more than one year of follow-up, number of 
patients with at least one reinjection and number of reinjections per patient during the follow-up 
year considered will be described for each year of follow-up (e.g. 2nd year of follow-up, 3rd year of 
follow-up…). The number and percentage of patients receiving each injection (first, second, etc.) 
will be presented for each year of follow-up. 
Time between Ozurdex implant injections will be summarized overall and for each reinjection, i.e. 
first reinjection, second reinjection… 
14.2.2.3  
Secondary Objectives 
14.2.2.3.1 
Relationship between Reinjection Intervals and Effectiveness 
Analysis will be performed considering each Ozurdex reinjection separately (second injection or first 
reinjection, third injection or second reinjection…) (see Figure 1). 
Change in BCVA from time of reinjection to 7-12 weeks following reinjection and change in BCVA 
from time of first injection to 7-12 weeks following reinjection will be summarized for each 
reinjection. The same analyses will be performed for the change in CRT. 
A first approach to assess the relationship between reinjections intervals and effectiveness will be 
to consider time interval between two injections (previous injection - reinjection) as a continuous 
parameter. The potential relationship between time interval and effectiveness will be assessed 
graphically using a scatter plot. Time interval between two injections (in months) will be plotted on 
the horizontal axis and either BCVA change or CRT change from time of reinjection to 7-12 weeks 
following reinjection will be plotted on the vertical axis. The corresponding correlation coefficients 
will be calculated. The same scatter plot will be done for the change in BCVA and CRT from time of 
first implant injection to 7-12 weeks following each Ozurdex implant injection. 

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Figure 1 Example of Reinjections Intervals and Effectiveness Outcomes Disposition in a Hypothetic 
Patient 
 
 
 
 
 
 
BCVA=Best corrected visual acuity; CRT=Central retinal thickness 
 
 
For "Time interval 1", BCVA and CRT change from measurement 1 to measurement 2 will be considered; for "Time interval 
2" BCVA and CRT change from measurement 3 to measurement 4 will be considered; and for "Time interval 3", BCVA and 
CRT change from measurement 5 to measurement 6 will be considered. 
 
A second approach will be to consider time interval between two injections as a categorical 
variable; either 2 categories will be considered based on median time interval or other categories 
will be considered based on observed distribution. BCVA change and CRT change from reinjection 
to 7-12 weeks following reinjection and BCVA and CRT change from time of first implant injection 
to 7-12 weeks following each Ozurdex implant injection will be described by these categories. 
14.2.2.3.2 
Reason for Ozurdex Implant Initial Injection and for Reinjection 
Reason for initial injection and for reinjection of Ozurdex implants will be summarized descriptively. 
14.2.2.3.3 
Drug Effectiveness in Patients Naïve of any Anti-VEGF Treatment 
Change in BCVA from time of reinjection to 7-12 weeks following reinjection and change in BCVA 
from time of first injection to 7-12 weeks following reinjection will be summarized for each 
reinjection considering the subgroup of patients who are treatment naïve of any anti-VEGF 
treatment. The same will be performed for the change in CRT. 
14.2.2.3.4 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) potentially related to Ozurdex reinjection will be 
summarized descriptively. Number and percentage of patients who experienced AESIs 
 
will be described overall 
. 
 
  
BCVA and CRT measured 7 to 12 weeks following each reinjection 
Last BCVA and CRT measured before injection of Ozurdex 
1st injection 
2nd injection or 
1st reinjection 
3rd injection or 
2nd reinjection 
4th injection or 3rd 
reinjection 
Time interval 1 
Time interval 3 
2 
4 
6 
1 
Time interval 2 
3 
5 

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15 
ETHICAL CONDUCT OF THE STUDY 
15.1 
Ethics Statement 
The study shall be conducted in compliance with International Society for Pharmacoepidemiology 
Good Pharmacoepidemiology Practice (ISPE GPP) guidelines21, the ethical principles arising from 
the Declaration of Helsinki revised in 201322, the European Union Good Pharmacovigilance practices 
(GVP)17, European and National laws in terms of data protection23 and all current local regulations. 
Relevant scientific guidelines such as ENCePP Guide on Methodological Standards in 
Pharmacoepidemiology24 will be considered. 
15.2 
Informed Consent 
Due to the retrospective and anonymous nature of data collection for this study, signature of 
informed consent by patients is not required to abstract data from the patient's chart. A waiver of 
consent will be requested from IECs. 
15.3 
Institutional Review Board / Independent Ethics Committee 
Approval 
This study is non-interventional. The drug used to treat the patient is based on clinical judgment 
alone, and, as such, does not come under applicable laws and regulation on clinical trials, as no 
drug is provided by the Sponsor or any third party. No specific examinations or laboratory tests are 
to be performed above and beyond those usually undertaken by the investigator, and no additional 
visits are required for study purposes. 
Submissions and/or notification to the appropriate IEC will be performed as required by local 
legislation in each country for this type of study. 
15.4 
Data Protection  
Patients' personal data and investigator's personal data shall be treated in compliance with the 
European Regulation23 on the protection of individuals with regard to the processing of personal 
data and all local applicable laws and regulations. 
Data about investigators will be declared to applicable data protection authority and the 
investigators will be informed – within the framework of the site qualification questionnaire – of 
their right to access to, rectify or erase data, or their right to restrict or object to processing of the 
data, as well as the right to data portability. 
Patient data will be anonymized, i.e. investigators will not be able to connect the patient with 
his/her identification number. The sponsor will be blinded to the patient information. 
Submission(s) to competent data protection authorities will be performed as appropriate. 
15.5 
Adherence to the Protocol 
The study must be conducted as described in the approved protocol. Any significant deviation from 
the protocol must be reported immediately to the Sponsor and IEC. 

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15.6 
Protocol Amendment 
Any amendment to the protocol will be created by the Sponsor, and subsequently submitted by the 
site to the IEC and appropriate regulatory authority for approval.  
15.7 
Retention of Patient Records 
When the study is completed, the investigators must retain the essential documents for as long as 
needed to comply with regulatory guidelines and Sponsor requirements. The investigators will 
notify the Sponsor prior to moving or destroying any of the study documents. 
The Sponsor will maintain the data collected (study database) for at least 5 years. 
15.8 
Confidentiality 
The information in this and related documents from the Study Sponsor includes trade secrets and 
commercial information that are confidential and may not be disclosed, unless such disclosure is 
required by federal or other laws or regulations. In any event, persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further disclosed by 
them. 
Individual patient medical information obtained as a result of this study is considered confidential, 
and disclosure to third parties, other than those noted below, is prohibited. Such medical 
information may be given to the patient's personal physician or to other appropriate medical 
personnel responsible for the patient's welfare. 
Data generated as a result of this study are to be available for inspection on request of the 
Sponsor's representative, the IEC, or local regulatory agency. 
16 
PLANS FOR DISSEMINTATING AND COMMUNICATING 
STUDY REPORT 
The Sponsor and/or designee will develop a final study report after the end of the study. Results 
will be posted on Clinical Trials.gov. 
This study is intended for publication, even if terminated prematurely. Publication may include any 
or all of the following: posting of a synopsis online, abstract and/or presentation at a scientific 
conference, or publication of a full manuscript. Authorship credit will follow the guidelines 
established by the International Committee of Medical Journals Editors25 and, as such, should be 
based on the following criteria 1) substantial contributions to the conception or design of the work; 
or the acquisition, analysis, or interpretation of data for the work; 2) drafting the work or revising 
it critically for important intellectual content; 3) final approval of the version to be published and 
4) agreement to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved. All 
authors must meet all above criteria. Although publication planning may begin before conducting 
the study, final decisions on authorship and the order of authors’ names will be made based on 
participation and actual contributions to the study and writing, as discussed above. 

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17 
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2. 
Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular 
edema and related vision loss.Eye Vis (Lond). 2015 Sep 30;2:17. 
3. 
Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, Sanchez JG, Wu L, Maia M, Berrocal MH, 
Solis-Vivanco A, Farah ME; Pan-American Collaborative Retina Study Group.Ophthalmology. 
Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: results from the Pan-
American Collaborative Retina Study Group at 6-month follow-up. 2007 Apr;114(4):743-50. 
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Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, Boos CJ, Xing W, 
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Schmidt-Erfurth U, Chong V, Loewenstein A, Larsen M, Souied E, Schlingemann R, Eldem B, 
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Ophthalmology. 2015 Oct;122(10):2044-52 
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Avery RL, Gordon GM. Systemic Safety of Prolonged Monthly Anti-Vascular Endothelial Growth 
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Chen YY, Chang PY, Wang JK. Intravitreal Aflibercept for Patients with Diabetic Macular Edema 
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Bhisitkul RB, Campochiaro PA, Shapiro H, Rubio RG.Predictive value in retinal vein occlusions 
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10. Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: pathogenesis and 
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11. Ghanchi F; Diabetic Retinopathy Guidelines Working Group. The Royal College of 
Ophthalmologists' clinical guidelines for diabetic retinopathy: a summary. Eye (Lond). 2013 
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12. Boyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RK, Augustin AJ, Li XY, Cui H, Hashad Y, 
Whitcup SM; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of 
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13. Mastropasqua R, Toto L, Borrelli E, Di Antonio L, De Nicola C, Mastrocola A, Di Nicola M, 
Carpineto P. Morphology and Function over a One-Year Follow Up Period after Intravitreal 
Dexamethasone Implant (Ozurdex) in Patients with Diabetic Macular Edema. PLoS One. 2015 
Dec 31;10(12):e0145663. 
14. ICH Topic E2D - Post Approval Safety Data Management. Note for guidance on definitions and 
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Chaikitmongkol V, Couturier A, Giancipoli E, Lupidi M, Rodríguez-Valdés PJ, Rehak M, Fung AT, 
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APPENDICES 
None