Randomized Trial Evaluating Bevacizumabe or Triamcinolone for Persistent Diabetic Macular Edema
Phase: PHASE2
Conditions: Diabetic Macular Edema
Sponsor: University of Sao Paulo

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TRIAL STUDY PROTOCOL (ENGLISH VERSION) 
 
 
 
 
Bevacizumab Versus Triamcinolone for 
Persistent Diabetic Macular Edema:  
A Randomized Clinical Trial 
 
 
 
Department of Ophthalmology – Ribeirao Preto Medical School   
University of Sao Paulo 
 
 
 
 
 
Ribeirao Preto  
2016 
 
 
 
 
 RIBEIRAO PRETO MEDICAL SCHOOL, UNIVERSITY OF SÃO 
PAULO 
Department of Ophthalmology 
3900, Bandeirantes avenue, zip: 14049-900 Ribeirão Preto city-SP 
e-mail:murilowrj@yahoo.com.br – Phone(16) 3602-2523 

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Conflict of Interest: None 
 
Authors’ Contributions: José Augusto Cardillo, M.D., Ph.D. and Rodrigo Jorge, 
M.D., Ph.D. are the primary contributors to the research design. Murilo Wendeborn 
Rodrigues, M.D., is responsible for research execution and data acquisition. André 
Messias, M.D., Ph.D., is the primary contributor to data analysis and interpretation. 
Manuscript preparation by Murilo Wendeborn Rodrigues, M.D., with revisions provided 
by José Augusto Cardillo, M.D., Ph.D., Rubens Camargo Siqueira M.D., Ph.D., Ingrid 
U. Scott, M.D., M.P.H., and Rodrigo Jorge, M.D., Ph.D. The project had financial 
support by CNPq government (National Research Council). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Main Investigator of Study 
 
 
Murilo Wendeborn Rodrigues Junior, physician and ophthalmologist – retina 
specialist. Post-Graduate student of Ribeirao Preto Medical School – University of Sao 
Paulo. 
 
Adress: 
36, Raul Silva st, apt 72, São Jose Do Rio Preto-city, São Paulo state. 
ZIP:15015-020. 
 
Cel. phone: 17-981698384 
 
E-mail: murilowrj@yahoo.com.br  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1. BACKGROUND 
1.1 Pathophysiology 
1.2 Treatment 
1.3 Triamcinolone and Clinical Applications 
  
2. OBJECTIVES 
2.1 Primary Objective 
2.2 Secondary Objective 
      
3. STUDY DESIGN 
3.1 Description of Study 
3.2 Rationale for Study Design 
3.3 Safety Plan 
3.4 Compliance with Laws and Regulations 
 
4. MATERIALS AND METHODS 
4.1 Subjects 
4.1.1 Subject Selection 
4.1.2 Inclusion Criteria 
4.1.3 Exclusion Criteria 
4.2 Method of Treatment Assignment 
4.3 Study Treatment 
4.4 Concomitant and Excluded Therapies 
4.5 Study Assessments 
4.5.1 Assessments during the Treatment Period 
4.5.2 Early Termination Assesments 
4.6 Subject Discontinuation 
4.7 Statistical Methods 
4.7.1 Analysis of the Conduct of the Study 
4.7.2 Efficacy Analyses 
4.7.3 Safety Analyses 
4.7.4 Missing Data 
4.7.5 Interinm Analyses 
 
5. ASSESSMENT OF SAFETY 
5.1 Adverse Events 
5.2 Baseline Medical Conditions 
5.2.1 Recording Adverse Events 
5.2.2 Special Reporting Situations 
5.2.3 Type and Duration of Follow-up After Adverse Events 
6. INVESTIGATOR REQUIREMENTS 
6.1 Study Initiation 
6.2 Informed Consent Form 
6.3 Institutional Review Board or Ethics Committee Approval 
6.4 Case Report Forms 
6.5 Study Drug Accountability 
6.6 Disclosure of Data 
6.7 Retention of Records 

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7. PAYMENTS, REMUNERATIONS AND COSTS TO PARTICIPANTS 
7.1  
PAYMENTS AND REMUNERATION 
7.2 
COSTS 
 
REFERENCES 
 
APPENDICES 
 
Appendix A: Study Flowchart 
Appendix B: Pre-Injection Procedures for All Subjects 
 
 
 
1. BACKGROUND 
 
1.1 PATHOPHYSIOLOGY 
 
In 2050, the prevalence of Diabetes mellitus (DM) will triplicate in the worldwide 
and imply certainly in an important concern of universal healthcare [1]. Diabetic 
retinopathy (DR) is prevalent in approximately 35% of diabetic patients and diabetic 
macular edema (DME) is the major cause of visual loss in patients with diabetes [2,3]. 
There is fewer epidemiologic data about DR in Brazil but general DR prevalence in 
Ribeirão Preto city, is about 29% for patients with type II DM and  29.9% for patients 
with type I DM [4-6] 
DME occurs due to a breakdown of the blood-retinal barrier with subsequent 
leakage of plasma and lipids in the macula. Hyperglycemia is thought to be the 
strongest risk factor contributing to the pathogenesis of DME due to its activation of 
pathways that lead to increased oxidative stress, inflammation, and vascular 
dysfunction.[7] The resulting oxidative stress and inflammation also lead to the up-
regulation of multiple cytokines and various growth factors, including VEGF, which 
then contribute to further breakdown of the blood-retinal barrier and the accumulation 
of fluid in the macula.[8] DME can occur in any stage of DR, including non-proliferative 
and proliferative DR. 
1.2 TREATMENT OF DIABETIC MACULAR EDEMA 
The Early Treatment of Diabetic Retinopathy Study (ETDRS) established the 
use of focal/grid photocoagulation for patients with clinically significant DME, resulting 
in a 50% reduction in severe vision loss for these patients.[9] With FDA approval of 
two anti-VEGF agents, focal/grid laser is now reserved for those with non-centrally-
involved DME, while anti-VEGF therapy is indicated for those with centrally-involved 
DME. Ranibizumab is an antibody fragment and bevacizumab is a full length antibody 
are that block VEGF-A and intraocular injections of these agents substantial improve 
vision in patients with DME.[10,11] Aflibercept (Eylea, Regeneron Pharmaceuticals, 
Inc., Tarrytown, NY, USA) is a 115-kDa fusion protein containing the binding domains 
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Two phase 3 parallel, double-masked, multicenter trials (VISTA and VIVID) compared 
aflibercept to focal/grid laser for DME.[12]  Patients (872) were randomization to 
intravitreal aflibercept 2 mg every 4 weeks, 2 mg every 8 weeks after 5 initial monthly 
doses, or focal/grid laser and at 1 year, mean improvement from baseline BCVA was 
42%, 31%, and 8%, respectively. Mean reduction in retinal thickness was 186, 183, 
and 73 µm, respectively. In the aflibercept groups, less than 10% required rescue 
laser treatment thereby limiting laser as a confounding influence on the visual gains. 
The visual acuity gains demonstrated in the aflibercept groups were sustained 
through week 100.[13] In DRCR.net protocol I, approximately 40% of eyes receiving 
ranibizumab injections with prompt or deferred focal/grid laser had a CSFT≥250 µm 
on time domain (TD) optical coherence tomography (OCT) at 2 years. [14] These 
data suggest that there may be VEGF-independent molecular mechanisms that are 
involved in the development and sustenance of macular edema. Thus, there is a need 
for alternative or additional treatments that will improve vision by reducing retinal 
edema in eyes with persistent DME following previous anti-VEGF therapy. Because 
corticosteroids have been demonstrated to inhibit the expression of both VEGF and 
the VEGF gene [15-17] and  utilized in DME due to their ability to inhibit inflammatory 
cytokine production a strong rationale exists for their use in the treatment of DME. In 
pseudophakic eyes, visual improvement at 1-year in patients receiving intravitreal 
triamcinolone plus prompt laser was comparable to that in groups receiving 
ranibizumab plus laser; however, by 2 years, the effects of corticosteroids plus laser 
were not superior to laser alone with regards to visual acuity or macular edema.[18] 
In a randomized multicenter trial, fluocinolone acetonide intravitreal inserts provided 
substantial visual improvement in patients with DME at 2 years.[19] Ozurdex, a 
dexamethasone intravitreal implant, has been shown to improve visual outcomes in 
patients in numerous studies.[20-22]  
1.3 Triamcinolone and Clinical Applications 
Triamcinolone acetonide (TA) is a synthetic corticosteroid formulated as an 
injectable suspension and has a 7.5-fold higher anti-inflammatory potency than 
cortisone.[23] Because TA is water insoluble, it can remain in the vitreous for much 
longer than other corticosteroids, which are usually eliminated within a few days. 
Because TA is water insoluble, it can remain in the vitreous for much longer than other 
corticosteroids, which are usually eliminated within a few days. In the protocol B 
(DRCR.net study) 3 groups of DME therapy was performed: 1-laser, 2-TA (1mg) and 
3-TA (4mg). After 3 years; 44%, 25% and 38% of patients had 10 or more letters 
improvement in BCVA respectively.[24]  Related to basal center subfield foveal 
thickness (CSFT): 67%, 43% and 51% of eyes had macular thickened to less than 
250µm after 3 years of treatment respectively.  
 
2. OBJECTIVES 
 
2.1 Primary 

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Patients who have residual edema after 6 months of pro re nata 
intravitreous 1.25mg (0.05cc) bevacizumab (prn-IVB) will be randomized to 
prn-IVB or 1.20mg (0.03cc) quarterly intravitreous TA (qIVT) and mean change 
from baseline and from randomization CSFT will be compared at 24 weeks 
after randomization. 
 
 
2.2 Secondary 
- 
To compare the mean change from baseline and randomization BCVA in 
the prn-IVB versus qIVT groups.  
- 
To compare the mean number of intravitreous injections between the prn-
IVB versus qIVT groups. 
- 
To compare effects on intraocular pressure (IOP) and need for IOP-lowering 
drops and/or surgery to reduce IOP between prn-IVB versus qIVT groups. 
 
3. STUDY DESIGN 
3.1 DESCRIPTION OF THE STUDY  
This trial study will enroll a total of 83 DME patients (115 eyes). Each patient will 
receive an injection of prn-IVB at baseline and as need monthly based on macular 
thickness through 6 months. At week 24, patients who have recurrent or persistent 
edema will be randomized 1:1 to Group 1 (prn-IVB) or Group 2 (qIVT). Patients with 
no recurrent or persistent edema at week 24 will comprise Group 3 and continue to 
receive prn-IVB every 4 weeks. Prn treatment will be administered when central 
subfield foveal thickness (CSFT) >300 µm. There will be a minimum interval of 12 
weeks between qIVT injections. 
Study visits will occur every 4 weeks with the primary endpoint at week 48. At each 
visit, patients will have an eye exam and CSFT, BCVA, and IOP will be assessed. 
Fundus photography and fluorescein angiography will also be performed at baseline, 
week 36, and week 48.  
Rescue therapy: If, after 3 consecutive injections, there was not a reduction in 
CSFT of at least 10% and/or an increase in BCVA of at least 5 letters compared with 
baseline, the patient could continue to receive the same intravitreal medication for an 
additional 3 consecutive visits or discontinue treatment. All patients will resume 
standard care after exiting. 
3.2 RATIONALE FOR STUDY DESIGN 
Despite the use of anti-VEGF therapy as first-line treatment for centrally 
involved DME, there are many patients whose response to therapy is poor or 
transient at best.[25] In the RISE/RIDE trials, approximately 50% of patients failed 
to achieve ≥ 15-letter gain in BCVA despite 2 years of monthly Ranibizumab (0.5 

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mg) injections.[26] In addition to the need to find effective alternative treatment 
strategies for patients with refractory DME, monthly injections can become 
burdensome for many patients. Given the key role of inflammation in the 
pathogenesis of DME, corticosteroids are frequently used as a treatment option 
due to their suppression of inflammatory cytokines.[27] In addition, corticosteroids 
suppress the expression of VEGF and may also function as neuroprotectants in 
the retina.[28] The FAME study group found that fluocinolone acetonide inserts in 
patients who previously had ≥ 1 macular laser treatment for DME provided 
substantial visual benefits for up to 3 years, with 28.7% of patients receiving the 
low-dose insert gaining ≥15 letters at month 36.[29] 
Our real life study seeks to assess the effects of Triamcinolone as one such 
alternative treatment option for patients with DME despite prior anti-VEGF therapy. 
We hope that our study will expand our knowledge on alternative treatment 
strategies for patients suffering from persistent DME. 
3.3 SAFETY PLAN 
The safety assessments to be conducted for this study are listed in Section 5 and 
Appendix B. 
Potential safety issues are associated with the route of administration of 
triamcinolone/bevacizumab, the pharmacology of triamcinolone, the pharmacology of 
bevacizumab, and fluorescein angiography. Subjects will be instructed to contact their 
physician at any time should they have health-related concerns. All adverse events 
(serious and non-serious) will be recorded for the duration of the study. 
Fluorescein Angiography 
Risk associated with fluorescein angiography (FA) may include bleeding and/or 
bruising at the site of the needle insertion, itching, rash, or vomiting.  A rare and severe 
allergic reaction can also occur during fluorescein angiography. Patients allergic to 
shellfish may be at risk for an allergic reaction to fluorescein or other dye. However, 
individuals with allergies to shellfish can receive a medication before the dye test to 
minimize allergic responses. Serious allergic reactions such as severe swelling and 
difficulty breathing can happen in 1 out of 10,000 patients and about 1 out of 222,000 
patients can have a heart attack, stroke, or even die from the fluorescein dye 
administration. If the patient has ever had a severe allergic reaction to fluorescein dye, 
he or she will not be included in the study. To minimize allergic reaction to fluorescein 
angiography, any patient who has had mild reactions to previous FA (e.g. itching) will 
be given medication prior to undergoing FA.  
 
Risk of Intravitreous Injections 
Intravitreous injection has a 0.1 to 0.2% risk of complications such as vitreous 
hemorrhage, retinal detachment, endophthalmitis (intraocular infection), intraocular 
hypertension, and cataract formation (in patients who have not had their cataract 

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removed). Repeated injections may increase this risk. However, the vast majority of 
patients tolerate repeated injections well.   
To minimize the risks of intravitreous injections, all injections will be performed 
employing standard surgical sterile techniques as described in Appendix B. All 
investigators in this trial have been instructed in this technique and are experienced in 
performing intravitreous injections.  Following each injection, subjects will have a 
retinal examination to ensure that there is good perfusion of retinal vessels.   
 
Plans to Decrease Potential Risks and Increase Safety 
We will use strict sterile technique for injection of triamcinolone/bevacizumab. Detailed 
ocular examinations (e.g., BCVA, IOP, slit lamp examination and dilated fundus 
examination) will be performed every month. Any subject who develops significantly 
raised intraocular pressure ( 30 mmHg) at any time during the study will be monitored 
according to the physician’s clinical judgment and may undergo additional 
measurements of intraocular pressure beyond those specified in the protocol. 
Pressure-lowering eye drops including Alphagan P (brimonidine tartrate ophthalmic 
solution) or Cosopt (dorzolamide hydrochloride-timolol maleate) may also be used. 
The Principal Investigator will review all adverse events. The appropriate IRB will be 
notified immediately of any serious adverse events and will be notified in yearly 
renewals of all other adverse events. The IRB and FDA will be notified of any 
interruption in enrollment or change in the conduct of the study.  
If subjects experience ocular inflammation that delays or causes discontinuation of 
intravitreal injections, appropriate IRBs and other relevant governing bodies will be 
notified. Study drug administration will be held for subjects who experience certain 
ocular events or infection events. In the event any subject develops an adverse event 
in the study eye that is considered by the designated evaluating physician to be severe 
in intensity, serious consideration should be given to withdrawing the subject from the 
study. Subjects withdrawn from the study prior to completion will be asked to return 
for an early termination evaluation 30 days (± 7 days) following their last injection/study 
visit for monitoring of all adverse events (serious and non-serious; ocular and non-
ocular).  
3.4 COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with current U.S. Food and Drug 
Administration (FDA) Good Clinical Practices (GCPs) as well as local ethical and 
legal requirements in Brazil. 
4. 
MATERIALS AND METHODS 
4.1 
SUBJECTS 
4.1.1 Subject Selection 

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83 eligible patients (115 eyes) with DME will be enrolled over a period of 12 months. 
Subjects will be identified and recruited through the clinic population of the study in 
Brazil.  
 
4.1.2 Inclusion Criteria 
 
All subjects must meet the following criteria to be eligible for study entry: 
• Signed informed consent and authorization of use and disclosure of 
protected health information. 
• Age 18 years. 
• Type 1 or type 2 diabetes. 
• Patients diagnosed with fovea-involved DME in the study eye, with 
CST >300 µm. 
• BCVA 20/32 to 20/400. 
• No history of treatment for DME in study eye for 4 months prior to 
enrollment, including anti-VEGF, focal/grid photocoagulation, 
intravitreal or peribulbar corticosteroids. 
 
4.1.3. Exclusion Criteria 
 
Subjects who meet any of the following criteria will be ineligible for study 
entry: 
• Evidence of permanent reduction in vision in study eye indicated by 
pigmentary abnormalities or some other structural abnormality (such as 
macular hole or significant epiretinal membrane) involving the fovea. 
• Macular edema due to a cause other than diabetes, such as from 
surgery or vitreoretinal interface abnormalities (e.g., epiretinal 
membrane). 
• Myocardial infarction, other acute cardiac event requiring 
hospitalization, stroke, transient ischemic attack, or treatment for acute 
congestive heart failure within 3 months of study entry. 
• For women of child-bearing potential: pregnant or lactating or intending 
to become pregnant within the next 24 months. Women who are 
potential study participants should be questioned about the potential 
for pregnancy. Potential child-bearing subjects will be instructed to use 
contraceptive methods. Investigator judgment is used to determine 
when a pregnancy test is needed.   

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• History of major ocular surgery (cataract extraction, scleral buckle, 
surgery for DME or any macular condition such as macular hole, any 
intraocular surgery, etc.) within the prior 4 months or anticipated within 
the next 6 months following randomization. 
• Confluent hard exudates involving the center of the fovea. 
• History of macula-off retinal detachment, irrespective of whether 
patient underwent successful surgery. 
• Aphakia. 
 
4.2      METHOD OF TREATMENT ASSIGNMENT 
This study will enroll 115 eyes, with pseudophakic and phakic subjects. All study 
subjects will receive prn bevacizumab at baseline and through initials 24 weeks. At 
week 24, each eye will be evaluated for macular edema, and those patients who have 
no recurrent or persistent edema will continue to receive prn bevacizumab (1.25 mg) 
every 4 weeks as part of Group 3. Those patients who have persistent edema at week 
24 will undergo 1:1 randomization within each subgroup to either prn bevacizumab  
(1.25 mg) every 4 weeks or quarterly triamcinolone (1.20 mg) every 12 weeks (Group 
1 and Group 2, respectively). Prn treatment will be administered when central subfield 
foveal thickness (CSFT) > 300 µm and/or there are intraretinal cystoid spaces in the 
fovea. There will be no placebo or sham treatment. There will be no masking; patients 
and physicians will know the assignments to each group.  
 
4.3      METHOD OF TREATMENT ASSIGNMENT 
 
Intravitreous injections of bevacizumab or triamcinolone will be carried out under 
controlled aseptic conditions, which include the use of gloves and a sterile eyelid 
speculum. Topical or subconjunctival anesthesia will be used based upon patient and 
physician preference. The site of injection will be sterilized with 5% povidone iodine. 
The needle will be through the pars plana 3.5-4.0 mm posterior to the limbus and the 
triamcinolone or bevacizumab will be injected into the vitreous cavity. Following the 
injection, patients will be examined by indirect ophthalmoscopy to make sure there is 
good perfusion of retinal vessels. Patients will be instructed to report any symptoms 
suggestive of endophthalmitis without delay. 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES 
      Any patient being treated for a serious systemic infection or an ocular 
infection in the study eye will be excluded.  Subjects may continue to receive 
all medications and standard treatments administered for their conditions at 
the discretion of their treating physician.   

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4.5 
STUDY ASSESSMENTS 
4.5.1 Assessments during the Treatment Period 
 
For a complete overview of the study assessments, see Flow Chart in Appendix 
A. 
Subjects will be followed monthly for a total of 48 weeks.  
 
Screening Visit (Day 0) 
• Obtain informed consent. 
• Record demographics, medical and ocular history, concomitant 
medications. 
• ETDRS BCVA (logMAR). 
• IOP (mmHg) measurement. 
• Slit lamp examination. 
• Indirect ophthalmoscopy. 
• Fundus photography. 
• Fluorescein angiography. 
• Measurement of foveal thickness by Spectralis OCT. 
If eligible, the patient may proceed to treatment  
 
Intraocular injection of bevacizumab. 
 
Weeks 4-20 
• ETDRS BCVA. 
• IOP measurement. 
• Slit lamp examination. 
• Indirect ophthalmoscopy. 
• Measurement of foveal thickness by Spectralis OCT. 
• Record concomitant medications. 
• Record adverse events. 
• Intraocular injection of bevacizumab 
 
Week 24 
• ETDRS BCVA. 
• IOP measurement. 
• Slit lamp examination. 

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• Indirect ophthalmoscopy. 
• Measurement of foveal thickness by Spectralis OCT. 
• Record concomitant medications. 
• Record adverse events. 
• Fundus photography. 
• Fluorescein angiography. 
• Randomization of patients with residual macular edema to bevacizumab 
(Group 1) or triamcinolone (Group 2). 
• Patients with no residual edema with not be randomized and will 
evaluated every 4 weeks and receive prn bevacizumab (Group 3) 
through week 48. 
 
GROUP 1 
Week 28-48 
• ETDRS BCVA. 
• IOP measurement. 
• Slit lamp examination. 
• Indirect ophthalmoscopy. 
• Measurement of foveal thickness by Spectralis OCT. 
• Record concomitant medications. 
• Record adverse events. 
• Intraocular injection of prn bevacizumab as per protocol. 
Within week-visit 36 and last week-visit 48: Include: 
• Fundus photography. 
• Fluorescein angiography. 
 
GROUP 2 
Week 28-48 
• ETDRS BCVA. 
• IOP measurement. 
• Slit lamp examination. 
• Indirect ophthalmoscopy. 
• Measurement of foveal thickness by Spectralis OCT. 
• Record concomitant medications. 
• Record adverse events. 
• Intraocular injection of quarterly triamcinolone as per protocol. 

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Within week-visit 36 and last week-visit 48: Include: 
• Fundus photography. 
• Fluorescein angiography. 
 
 
GROUP 3 
Week 28-48 
• ETDRS BCVA. 
• IOP measurement. 
• Slit lamp examination. 
• Indirect ophthalmoscopy. 
• Measurement of foveal thickness by Spectralis OCT. 
• Record concomitant medications. 
• Record adverse events. 
• Intraocular injection of prn bevacizumab as per protocol. 
Within week-visit 36 and last week-visit 48: Include: 
• Fundus photography. 
• Fluorescein angiography. 
 
4.5.2 Early Termination Assessments 
Subjects who withdraw from the study prior to completion should return for an 
early termination evaluation 30 days ( 14 days) following the last 
injection/study visit for monitoring of all adverse events (serious and non-
serious). The schedule of assessments for early termination is the same as 
that for the final visit. 
4.6 SUBJECT DISCONTINUATION 
Subjects have a right to withdraw from the study at any time.   
The subject may be withdrawn from the study for any reason: if it is in the best 
interest of the subject, concurrent illness, adverse events, or a worsening 
condition. Participating centers in the trial may request the withdrawal of a 
subject because of protocol violations, administrative reasons, or any other 
valid and ethical reasons.   
If a subject discontinues from the study, he or she will not be allowed to re-enter 
the study. 
Reasons for subject discontinuation may include, but are not limited to, the 
following: 

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• Rhegmatogenous retinal detachment or Stage 3 or 4 macular 
hole. 
• Investigator determination that it is not in the best interest of the 
subject to continue participation. 
• Pregnancy. 
• Serious adverse event (SAE). 
• Any other safety concerns. 
 
4.7 STATISTICAL METHODS 
4.7.1 Analysis of the Conduct of the Study 
This study will provide data on the effects of prn bevacizumab and quarterly 
triamcinolone on CSFT, BCVA, and IOP in patients with persistent DME 
despite receiving prior anti-VEGF therapy.  
4.7.2  Efficacy Analyses 
 
Primary Outcome Measure 
• Mean change from baseline and from randomization CSFT at week 48.  
Secondary Outcome Measures 
• Mean change from baseline and from randomization BCVA at week 48. 
• Mean change from baseline and from randomization IOP at week 48. 
 
4.7.3 Safety Analyses 
    Adverse events and results of ocular examinations from all 83 patients will be 
utilized to summarize safety data. The following outcomes will be assessed: 1) 
Percentage of eyes with IOP ≥ 25 or 30 mm Hg at any visit, 2) Percentage of eyes 
requiring IOP-lowering drops or surgery to reduce IOP at any visit, 3) Percentage of 
patients with significant worsening of cataract in the study eye during the study. 
4.7.4 Missing Data 
Analyses of efficacy and safety will be based on available cases without 
imputation for missing values. 
4.7.5 Interim Analyses 
No formal schedule of interim analyses is planned.  Reports of adverse 
events from this study may be reviewed and summarized periodically while the 
study is ongoing to ensure the safety of subjects.   

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5. 
ASSESSMENT OF SAFETY 
5.1 
ADVERSE EVENTS 
AEs that start on Day 0 through the last study visit will be recorded on 
the appropriate AE pages of the CRF. Subjects discontinuing early from the 
study should return for an early termination evaluation and will be contacted 
30 days after their last injection or study visit to assess for adverse events 
(serious and non-serious). 
For this protocol, an AE is any “on study” untoward medical occurrence 
(e.g., sign, symptom, disease, syndrome, concurrent illness) that occurs in a 
study subject, regardless of the suspected cause. “On study” refers to Day 0 
through the last study visit. 
Unchanged, chronic conditions are NOT AEs and should not be recorded on 
the AE pages of the CRF. An exacerbation or worsening of a chronic condition 
should be recorded as an AE. 
Both serious and non-serious AEs should be graded on a three-point scale 
(mild, moderate, severe) and reported in detail on the appropriate AE page of 
the CRF.   
The suggested definitions are as follows:  
Mild: 
Discomfort without disruption of normal daily activity. 
Moderate: 
Discomfort sufficient to reduce or affect normal daily 
activity. 
Severe: 
Incapacitating discomfort with inability to work or perform normal 
daily activity. 
Using the following criteria, investigators also need to assess whether there is 
a reasonable possibility that study drug caused or contributed to the AE. 
• Yes (possibly or probably): 
There is a clinically plausible time sequence between onset of the AE 
and study drug administration; and/or 
There is a biologically plausible mechanism for study drug causing or 
contributing to the AE; and 
The AE may or may not be attributed to concurrent/underlying illness, 
other drugs, or procedures. 
• No 
A clinically plausible temporal sequence is inconsistent with the onset 
of the AE and study drug administration; and/or 

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A causal relationship is considered biologically implausible. 
 
 
5.2 
BASELINE MEDICAL CONDITIONS 
It is not necessary to complete an AE CRF page for chronic medical 
conditions present at enrollment that do not worsen in intensity or frequency 
during the trial.  These medical conditions should be adequately documented 
on the appropriate page of the CRF (medical history and/or physical 
examination). However, medical conditions present at enrollment that worsen 
in intensity or frequency during the treatment or post-treatment periods and 
ongoing AEs that started during the previous study should be reported and 
recorded as AEs.   
5.2.1 Serious Adverse Events 
An AE occurring at any dose (including overdose) should be classified 
as SERIOUS if: 
• It resulted in death (i.e., the AE caused or led to death). 
• It was life threatening (i.e., the AE placed the subject at 
immediate risk of death; it does not apply to an AE that 
hypothetically might have caused death if it were more severe). 
• It required or prolonged inpatient hospitalization (i.e., the AE 
required at least a 24-hour inpatient hospitalization or prolonged 
a hospitalization beyond the expected length of stay; 
hospitalizations 
for 
elective 
medical/surgical 
procedures, 
scheduled treatments, or routine check-ups are not SAEs by this 
criterion). 
• It was disabling (i.e., the AE resulted in a substantial disruption 
of the subject’s ability to carry out normal life functions). 
• It resulted in a congenital anomaly/birth defect (i.e., an adverse 
outcome in a child or fetus of a subject exposed to the molecule 
or study drug prior to conception or during pregnancy). 
• It does not meet any of the above serious criteria but may 
jeopardize the subject or may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
Sight-threatening adverse events 
An adverse event is considered to be sight-threatening if it meets one or more 
of the following criteria and will be reported as a serious adverse event (SAE): 

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• The event causes a decrease in visual acuity of greater >30 letters 
(compared with the last assessment of visual acuity prior to the most 
recent treatment) lasting >1 hour. 
• The event causes a decrease in visual acuity to the level of light 
perception or worse lasting >1 hour. 
• The event requires surgical intervention (e.g, conventional surgery, 
vitreous tap or biopsy with intravitreal injection of antibiotics, or laser or 
retinal cryopexy with gas) to prevent permanent loss of sight. 
• The event is associated with severe intraocular inflammation (i.e., 4+ 
anterior chamber cell/flare or 4+ vitritis). 
• In the opinion of the investigator, the event may require medical 
intervention to prevent permanent loss of sight. 
 
SAE Reporting 
Sub-Investigators should report all SAEs to the Principal Investigator (PI) within 
48 hours of observing or learning of the event.  For initial SAE reports, 
investigators should record all case details that can be gathered within 
48 hours on the SAE page of the CRF. 
It is requested that the PI report the following events to Reading Center within 
7 days: unexpected, drug-related fatal or life threatening SAEs. 
It is requested that the PI report the following events to Reading Center within 
15 days: events of special interest (e.g. endophthalmitis, catastrophic 
outcomes such as enucleation, stroke). 
The completed SAE page and SAE Fax Cover Sheet should be faxed 
immediately upon completion to Reading Center 
Relevant follow-up information should be submitted to Reading Center as soon 
as it becomes available. 
 
5.2.2 Special Reporting Situations 
a. Death 
Death is an outcome of an event. The event that resulted in death 
should be recorded and reported on the SAE pages of the CRF. 
b. Hospitalizations for Surgical or Diagnostic Procedures 
The illness leading to the surgical or diagnostic procedure should be 
recorded as the SAE, not the procedure itself. The procedure should be 
captured in the case narrative as part of the action taken in response to 
the illness. 

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c. Pregnancy 
Any pregnancy occurring during study treatment should be reported, and the 
subject may be removed according to the discretion of the Principal 
Investigator. 
 
5.2.3 
Type And Duration Of Follow-Up After Adverse Events 
All reported AEs should be followed until resolution or until the subject’s 
participation in the study ends. Subjects who have an ongoing study drug–
related SAE at study completion or at discontinuation from the study will be 
followed by the investigator or his or her designee until the event is resolved or 
determined to be irreversible, chronic, or stable by the investigator.   
 
6.0 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file:  
• Current curricula vitae of the Principal Investigators. 
• Written documentation of IRB approval of protocol and informed 
consent document. 
• A copy of the IRB-approved informed consent document. 
• Written documentation of IRB review and approval of any 
advertising materials to be used for study recruitment, if 
applicable. 
• Certified translations of IRB approval letters, pertinent 
correspondence, and approved informed consent document 
(when applicable). 
• Current laboratory certification of the laboratory performing the 
analysis as well as current normal laboratory ranges for all 
laboratory tests. 
 
6.2      INFORMED CONSENT 
Informed consent documents will be provided to each subject.  
The informed consent document must be signed and dated by the subject or 
the subject’s legally authorized representative before his or her participation in 
the study. The case history for each subject shall document that informed 
consent was obtained prior to participation in the study. A copy of the informed 

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consent document must be provided to the subject or the subject's legally 
authorized representative. If applicable, it will be provided in a certified 
translation of the local language. 
Signed consent forms must remain in each subject’s study file and must be 
available for verification at any time. 
The following basic elements must be included: 
• A statement that the study involves research, an explanation of 
the purposes of the research and the expected duration of the 
patient’s participation, a description of the procedures to be 
followed, and identification of any procedures or drug used for 
purposes which are experimental. 
• A description of any reasonably foreseeable risks or discomforts 
to the patients. 
• A description of any benefits to the patient or to others that may 
reasonably be expected from the research. A description that 
there may be no benefit from this research. 
• A disclosure of appropriate alternative procedures or courses of 
treatment, if any, that might be advantageous to the patient. 
• A statement describing the extent, if any, to which confidentiality 
records identifying the patient will be maintained and that notes 
the possibility that the national and local health authorities and 
drug manufacturer may inspect the records. 
• For research involving more than minimal risk, an explanation as 
to whether any compensation and any medical treatments are 
available should injury occur and, if so, what they consist of or 
where further information may be obtained. 
• An explanation of whom to contact for answers to pertinent 
questions about the research and patients’ rights, and whom to 
contact in the event of a research-related injury to the patient. 
• A statement that participation is voluntary, that refusal to 
participate will involve no penalty or loss of benefits to which the 
patient is otherwise entitled, and that the patient may discontinue 
participation at any time without penalty or loss of benefits to 
which the patient is otherwise entitled. 
 

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6.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
APPROVAL 
This protocol, the informed consent document, and relevant supporting 
information must be submitted to the IRB/EC for review and must be approved 
before the study is initiated. The study will be conducted in accordance with 
applicable national and local health authorities, and IRB/EC requirements. 
The Principal Investigator is responsible for keeping the IRB/EC apprised of 
the progress of the study and of any changes made to the protocol as deemed 
appropriate, but in any case the IRB/EC must be updated at least once a year.  
The Principal Investigator must also keep the IRB/EC informed of any 
significant adverse events. 
Investigators are required to promptly notify their respective IRB/EC of all 
adverse drug reactions that are both serious and unexpected. This generally 
refers to serious adverse events that are not already identified in the 
Investigator Brochure and that are considered possibly or probably related to 
the study drug by the investigator.  Some IRBs or ECs may have other specific 
adverse event requirements that investigators are expected to adhere to. 
Investigators must immediately forward to their IRB/EC any written safety 
report or update. (e.g., Investigator Brochure, safety amendments and 
updates, etc.). 
 
6.4 
CASE REPORT FORMS 
All CRFs should be filled out completely by appropriate personnel.  The CRF 
should be reviewed, signed, and dated by the investigator. 
All CRFs should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced CRF 
copies. When making changes or corrections, cross out the original entry with 
a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, 
OR USE CORRECTION FLUID ON THE ORIGINAL. 
 
6.5 
STUDY DRUG ACCOUNTABILITY 
The Investigator is responsible for the control and distribution of the study drug. 
All partially used or empty containers should be disposed of at the study site 
according to institutional standard operating procedure.  
 

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6.6 
DISCLOSURE OF DATA 
Subject medical information obtained by this study is confidential, and 
disclosure to third parties other than those noted below is prohibited. 
Upon the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his 
or her welfare. 
Data generated by this study must be available for inspection upon request by 
representatives of the national and local health authorities, the drug 
manufacturer and the IRB/EC for each study site, if appropriate. 
6.7 
RETENTION OF RECORDS 
The Principal Investigators will retain records for 2 years after the investigation 
is discontinued. 
 
7. 
PAYMENTS, REMUNERATIONS AND COSTS TO PARTICIPANTS 
7.1  
PAYMENTS AND REMUNERATION 
There is no compensation for participants in this study.  
7.2 
COSTS 
There are no costs for study procedures or study drugs to participants. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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REFERENCES 
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Endocrinol Diabetes Obes 19(2):93–96. 
2. Federation, I.D. IDF Diabetes, 7 ed. 2015. 
3. Yau, J.W., et al., Global prevalence and major risk factors of diabetic 
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the University of Ribeirão Preto, São Paulo – USP. Arq Bras Oftalmol 67, 6. 
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6. Pimazoni A. (2008). Dados Recentes Reacendem a Polêmica Sobre o Número 
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sbd/debates. 
7. Das, A., P.G. McGuire, and S. Rangasamy, Diabetic Macular Edema: 
Pathophysiology and Novel Therapeutic Targets. Ophthalmology, 2015. 
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8. Miyamoto, K., et al., Vascular endotelial growth fator (VEGF)-induced retinal 
vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-
1). Am J Pathol, 2000. 156(5): p. 1733-9. 
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Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy 
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10. Rajendram, R., et al., A 2-year prospective randomized controlled trial of 
intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic 
macular edema: 24-month data: report 3. Arch Ophthalmol, 2012. 130(8): p. 
972-9. 
11. Brown, D.M., et al., Long-term outcomes of ranibizumab therapy for diabetic 
macular edema: the 36-month results from two phase III trials: RISE and RIDE. 
Ophthalmology, 2013. 120(10): p. 2013-22. 
12. Korobelnik, J.F., et al., Intravitreal aflibercept for diabetic macular edema. 
Ophthalmology, 2014. 121(11): p. 2247-54. 
13. Brown, D.M., et al., Intravitreal Aflibercept for Diabetic Macular Edema: 100-
Week Results From the VISTA and VIVID Studies. Ophthalmology, 2015. 
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14. Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, et al; 
Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of 
ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser 
for diabetic macular edema. Ophthalmology. 2011; 118(4):609-614. 
15. Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M. 
Corticosteriods inhibit the expression of the vascular endothelial growth factor 
gene in human vascular smooth muscle cells. Euro J Pharmacol. 1998;341(2-
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16. Nauck M, Roth M, Tamm M, Eickelberg O, Wieland H, Stulz P, et al. Induction 
of vascular endothelial growth factor by platelet-activating factor and platelet-
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17. Miyamoto K, Khosrof S, Moromizato Y, Aiello LP, Ogura Y, Adamis AP, et al. 
Vascular 
endothelial 
growth 
factor 
(VEGF)-induced 
retinal 
vascular 
permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J 
Pathol. 2000;156(5):1733-9. 

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18. lman, M.J., et al., Randomized trial evaluating ranibizumab plus prompt or 
deferred laser or triamcinolone plus prompt laser for diabetic macular edema. 
Ophthalmology, 2010. 117(6): p. 1064-1077 e35. 
19. Campochiaro, P.A., et al., Long-term benefit of sustained-delivery fluocinolone 
acetonide vitreous inserts for diabetic macular edema. Ophthalmology, 2011. 
118(4): p. 626-635 e2. 
20. Boyer, D.S., et al., Three-year, randomized, sham-controlled trial of 
dexamethasone intravitreal implant in patients with diabetic macular edema. 
Ophthalmology, 2014. 121(10): p. 1904-14. 
21. Haller, J.A., et al., Randomized controlled trial of an intravitreous 
dexamethasone drug delivery system in patients with diabetic macular edema. 
Arch Ophthalmol, 2010. 128(3): p. 289-96. 
22. Kuppermann, B.D., et al., Randomized controlled study of an intravitreous 
dexamethasone drug delivery system in patients with persistent macular 
edema. Arch Ophthalmol, 2007. 125(3): p. 309-17. 
23. Mansoor S, Kuppermann BD, Kenney MC. Intraocular sustained-release 
delivery systems for triamcinolone acetonide. Pharm Res 2009;26:770–784. 
24. The Diabetic Retinopathy Clinical Research Network. Three-year Follow Up of 
a Randomized Trial Comparing Focal/Grid Photocoagulation and Intravitreal 
Triamcinolone for Diabetic Macular Edema. (2009) 
25. Fraser-Bell, S., et al., Bevacizumab or Dexamethasone Implants for DME: 2-
year Results (The BEVORDEX Study). Ophthalmology, 2016. 
26. Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Long-
term outcomes of ranibizumab therapy for diabetic macular edema: the 36-
month results from two phase III trials: RISE and RIDE. Ophthalmology, 
2013;120(10):2013-22. 
27. Das, A., P.G. McGuire, and S. Rangasamy, Diabetic Macular Edema: 
Pathophysiology and Novel Therapeutic Targets. Ophthalmology, 2015. 
122(7): p. 1375-94. 
28. Miyamoto, K., et al., Vascular endothelial growth factor (VEGF)-induced 
retinal vascular permeability is mediated by intercellular adhesion molecule-1 
(ICAM-1). Am J Pathol, 2000. 156(5): p. 1733-9. 
29. Campochiaro PA, Brown DM, Pearson A, et al. FAME Study Group. 
Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for 
at least 3 years in patients with diabetic macular edema.Ophthalmology. 2012 
Oct;119(10):2125-32. doi:10.1016/j.ophtha.2012.04.030. Epub 2012 Jun 21. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A: STUDY FLOW CHART 
 
 
Baseline 
W4 
W8 
W12 
W16 
W20 
W24 
(Random) 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical 
History/Medications 
X 
X 
X 
X 
X 
X 
X 
ETDRS BCVA 
X 
X 
X 
X 
X 
X 
X 
IOP 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Exam 
X 
X 
X 
X 
X 
X 
X 
Fundoscopic Exam 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
OCT 
X 
X 
X 
X 
X 
X 
X 
Fluorescein Angiography 
X 
 
 
 
 
 
X 
Fundus Photography 
X 
 
 
 
 
 
X 
Prn-IVB (all) 
X 
X 
(prn) 
X 
(prn) 
X 
(prn) 
X 
(prn) 
X 
(prn) 
X 
(prn) 
Prn-IVB:  
Group 1  
Group 3 
 
- 
- 
 
- 
- 
 
- 
- 
 
- 
- 
 
- 
- 
 
- 
- 
 
- 
- 
IVT: Group 2 
(quarterly as need) 
- 
- 
- 
- 
- 
- 
- 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
 
 
W28 
W32 
W36 
W40 
W44 
W48 
 
 
 
 
 
 
 
Informed Consent 
 
 
 
 
 
 
Eligibility Criteria 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
Medical 
History/Medications 
X 
X 
X 
X 
X 
X 
ETDRS BCVA 
X 
X 
X 
X 
X 
X 
IOP 
X 
X 
X 
X 
X 
X 
Slit Lamp Exam 
X 
X 
X 
X 
X 
X 
Fundoscopic Exam 
X 
X 
X 
X 
X 
X 
OCT 
X 
X 
X 
X 
X 
X 
Fluorescein 
Angiography 
 
 
X 
 
 
X 
Fundus Photography 
 
 
X 
 
 
X 
Prn-IVB (all) 
- 
- 
- 
- 
- 
- 
Prn-IVB:  
Group 1 (transient) 
Group 3 (responder) 
 
X 
- 
 
X(prn) 
X(prn) 
 
X(prn) 
X(prn) 
 
X(prn) 
X(prn) 
 
X(prn) 
X(prn) 
 
- 
- 
qIVT: Group 2 
(quarterly as need) 
X 
- 
- 
X(prn) 
X(prn) 
- 
Adverse Events 
X 
X 
X 
X 
X 
X 
 

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APPENDIX B 
 
Pre-Injection Procedures for All Subjects 
 
The following procedures will be used to minimize the risk of potential adverse events 
associated with intravitreal injections (e.g., endophthalmitis). Aseptic technique will be 
observed by clinic staff involved in the injection tray assembly, anesthetic preparation, 
and study drugs’ preparation and administration. In addition to the procedures outlined 
below, any additional safety measures in adherence to specific institutional policies 
associated with intravitreal injections will be observed. 
The following procedures (except where noted) will be conducted by the physician 
performing the intravitreal injection of the study drugs.   
At the discretion of the investigator, the site may use either ophthalmic drops 
or lidocaine injection for study eye anesthesia. 
If using propacaine- tetracaine-or lidociane -based ophthalmic drops for anesthesia, 
the injecting physician or technician (if applicable) assembles the supplies and 
prepares a sterile field.  Supplies include 10% povidone iodine swabs, sterile surgical 
gloves, a pack of sterile cotton-tipped applicators, eyelid speculum, 5% povidone 
iodine ophthalmic solution, and injection supplies.  Note: The use of generic 
formulations or next-generation formulations of the antimicrobials listed above is 
permitted.  
Procedure for Anesthesia: 
• Instill two drops proparacaine or tetracaine-based ophthalmic drops into the study 
eye 
• Wait 90 seconds. 
• Instill two drops of 5% povidone iodine ophthalmic solution in the study eye, 
ensuring that the drops cover the planned injection site on the conjunctiva. 
• Wait 90 seconds. 
• Instill two more drops of proparacaine- or tetracaine-based ophthalmic drops into 
the study eye. 
• The physician will glove and place the speculum underneath the eyelid of the study 
eye. 
• Use 10% povidone iodine swabs to thoroughly clean the area of the conjunctiva 
that will be penetrated. 
• Saturate a sterile, cotton-tipped applicator with proparacaine- or tetracaine-or 
lidocaine -based drops and hold the swab against the planned intravitreal injection 
site for 60 seconds. 
• Instruct patient to direct gaze away from syringe prior to IVB or IVT injection.