Prevention of Macular Edema In Patients With Diabetic Retinopathy Undergoing Cataract Surgery
Phase: PHASE1
Conditions: Diabetic Retinopathy
Sponsor: Rishi Singh

 
 
 
 
 
 
 
 
 
Clinical Study Protocol 
Prevention Of Macular Edema In Patients With Diabetic Retinopathy Undergoing 
Cataract Surgery 
 
NCT01988246 
 
Document Date 
25JUL2018 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Clinical Study Protocol 
Prevention Of Macular Edema In Patients With Diabetic Retinopathy Undergoing 
Cataract Surgery 
 
 
Drug: 
Intravitreal Aflibercept Injection 
 
 
 
Study Name: 
Prevention Of Macular Edema In Patients 
With Diabetic Retinopathy Undergoing 
Cataract Surgery (The PROMISE Trial) 
 
 
Clinical Phase: 
Phase I/II 
 
 
Date of Issue: 
April 29th, 2013; October 10, 2014; 
October 27,2014; May 7, 2015;  
May 13, 2015; June 24, 2015; 
December 6, 2016, October 31, 2017, July 
25, 2018 
 
 
Primary Investigator: 
Richard Gans, M.D. 
 
 
 
 

 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
 
TITLE 
Prevention Of Macular Edema In Patients With 
Diabetic Retinopathy Undergoing Cataract Surgery 
TITLE IN LAY TERMS 
Prevention of macular edema in patients with 
diabetic retinopathy undergoing cataract surgery with 
Intravitreal Aflibercept Injection 
SITE LOCATION(S) 
Principal Investigator 
Cleveland, Ohio  
Richard Gans, M.D. 
OBJECTIVE(S) 
To determine the safety and efficacy of intravitreal 
Aflibercept injection in patients with diabetic 
retinopathy in the prevention of macular edema 
following cataract surgery.   
STUDY DESIGN 
This is a prospective randomized trial in patients with 
a history of diabetic retinopathy who are undergoing 
cataract surgery. Patients will be sequentially 
randomized to either intravitreal Aflibercept injection 
or Sham  
STUDY DURATION 
Duration of treatment: 90 Days 
Duration of Assessment: 90 days following surgery 
ESTIMATED STUDY 
COMPLETION DATE 
December 2018 
POPULATION 
 
 
Sample Size: 
30 patients 
Target Population: 
Diabetic retinopathy patients who are at risk of 
developing macular edema (defined as ≥ 30 % 
increase from pre-operative baseline in central 
subfield macular thickness) within 90 days following 
cataract surgery. Diabetic patients are defined as 
those who have either Type 1 or Type 2 diabetes.   
The patients must have either mild, moderate, or 
severe non proliferative retinopathy or treated 

 
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proliferative retinopathy.  Patients must be 18 years 
of age and older, of any race and either sex, requiring 
cataract extraction with planned implantation of a 
posterior chamber intraocular lens into the lens 
capsule. 
 
TREATMENT(S) 
 
 
Study Drug  
Intravitreal Aflibercept Injection 
Concurrent Control 
Sham injection (defined as pressing the needle less 
syringe against the eye). 
 
Masking 
Patient masked only 
ENDPOINT(S) 
 
 
Primary: 
 
Incidence and severity of ocular and non-ocular 
adverse events (AEs) and serious AEs between 
treatment arms.   
 
 
Secondary: 
 Percentage of patients who develop macular 
edema within 90 days following cataract surgery.  
This is defined as any of the following: 
o ≥30% increase from pre-operative baseline 
in central subfield macular thickness as 
measured by SD-OCT 
o 2 consecutive measurements (up to 7 days 
apart) with one of the following: 
 BCVA decrease of >5 E-ETDRS 
letters from the Day 7 
postoperative visit, AND 
 visual acuity loss due to retinal 
thickening based on the medical 
judgment of the investigator 
o Presence of cystoid abnormalities as 
detected by SD-OCT at any visit 
 Mean change from baseline in best-corrected 
visual acuity (BCVA) score at Day 90 
 Changes in macular volume and central retinal 
thickness from preoperative assessment to Day 90 
 Percentage of patients with a best corrected visual 
acuity (BCVA) decrease of › 5 E-ETDRS letters 
from Day 7 postoperative visit 
 Percentage of patients with greater than 15 letters 
of visual gain at Day 90 

 
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 Percentage of subjects with a loss of 15 letters or 
more of vision at Day 90 
 Step changes in diabetic retinopathy scale using 
the ETDRS definitions 
 Percentage of patients that are 20/40 or better at 
Day 90 
Percentage of patients that are 20/200 or worse at 
Day 90 
 
PROCEDURES AND 
ASSESSMENTS 
Ongoing safety assessments will include ophthalmic 
examinations and recording and evaluation of clinical 
adverse events.  Ongoing efficacy assessments will 
include SD-OCT measurements and E-ETDRS visual 
acuity measurements. 
STATISTICAL PLAN 
Demographic and baseline characteristics will be 
summarized descriptively by treatment group. Continuous 
variables will be summarized with mean, median, standard 
deviation, minimum, and maximum.  Categorical 
variables will be summarized with frequency and 
percentage. 
 
 
 
 

 
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TABLE OF CONTENTS 
Clinical Study Protocol Synopsis ..................................................................................... 3 
List of Tables ..................................................................................................................... 8 
1. Introduction and Rationale ....................................................................................... 9 
1.1 Introduction ................................................................................................................ 9 
1.2 Rationale .................................................................................................................. 10 
1.2.1 Rationale for Study Design ........................................................................... 10 
1.2.2 Rationale for Dose Selection ........................................................................ 11 
2. Study Objectives....................................................................................................... 11 
2.1 Primary Objective .................................................................................................... 11 
2.2 Secondary Objective(s) ............................................................................................ 11 
3. Study Design ............................................................................................................. 12 
3.1 Study Description and Duration............................................................................... 12 
3.2 Planned Interim Analysis ......................................................................................... 12 
4. Selection, Withdrawal, and Replacement of Patients ........................................... 13 
4.1 Number of Patients Planned ..................................................................................... 13 
4.2 Study Population ...................................................................................................... 13 
4.2.1 Inclusion Criteria .......................................................................................... 13 
4.2.2 Exclusion Criteria ......................................................................................... 14 
4.3 Premature Withdrawal from the Study .................................................................... 16 
4.4 Replacement of Patients ........................................................................................... 16 
5. Study Treatments ..................................................................................................... 17 
5.1 Dose Modification and Stopping Rules ................................................................... 17 
5.1.1 Dose Modification ........................................................................................ 17 
5.1.2 Study Drug Stopping Rules .......................................................................... 17 
5.2 Method of Treatment Assignment ........................................................................... 17 
5.2.1 Masking ......................................................................................................... 17 
5.3 Treatment Logistics and Accountability .................................................................. 18 
5.3.1 Packaging, Labeling, and Storage ................................................................. 18 
5.3.2 Supply and Disposition of Treatments .......................................................... 19 
5.3.3 Treatment Accountability ............................................................................. 19 
5.3.4 Treatment Compliance .................................................................................. 19 

 
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5.4 Concomitant Medications and Procedures............................................................... 20 
5.4.1 Permitted Medications and Procedures ......................................................... 20 
5.4.2 Prohibited Medications and Procedures ........................................................ 20 
5.5 Post-Study Treatment............................................................................................... 20 
6. Study Schedule of Events and Visit Descriptions ................................................. 21 
6.1 Schedule of Events ................................................................................................... 21 
6.2 Study Visit Descriptions .......................................................................................... 23 
6.2.1 Screening (Day –4 weeks to Day -2) with the retina specialist .................... 23 
6.2.1.1 
Day 0 (Surgery Visit) ............................................................................. 24 
6.2.2 Day 1 (± 1 day) 
 
 
 
 
 
 
 
       24 
6.2.3   Day 7, Day 14, Day, 30, and Day 60  
 
 
 
 
       25 
6.2.4 End of Study Visit/Early Termination/ Day 90 (± 7 days) by the cataract 
surgeon ...................................................................................................................... 26 
6.2.5 Early Termination Visit ................................................................................ 26 
6.2.6 Unscheduled Visits ....................................................................................... 28 
6.3 Study Procedures ..................................................................................................... 27 
6.3.1 Efficacy Procedures ...................................................................................... 27 
6.3.2 Safety Procedures .......................................................................................... 29 
6.3.2.1 Adverse Event Information Collection .................................................. 29 
7. Safety Definitions, Reporting, and Monitoring ..................................................... 28 
7.1 Definitions................................................................................................................ 28 
7.1.1 Adverse Event ............................................................................................... 28 
7.1.2 Serious Adverse Event .................................................................................. 29 
7.2 Recording and Reporting Adverse Events ............................................................... 30 
7.2.1 Deaths ........................................................................................................... 30 
7.2.2 Pregnancy and Other Events that Require Accelerated Reporting ............... 31 
7.2.3 Reporting Adverse Events Leading to Withdrawal from the Study ............. 31 
7.2.4 Abnormal Vital Signs Results ....................................................................... 32 
7.2.5 Follow-up ...................................................................................................... 32 
7.3 Evaluation of Severity and Causality ....................................................................... 33 
7.3.1 Evaluation of Severity ................................................................................... 33 
7.3.2 Evaluation of Causality ................................................................................. 34 
8. Study Variables ........................................................................................................ 34 

 
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8.1 Demographic and Baseline Characteristics ............................................................. 34 
8.2 Primary and Secondary Endpoints ........................................................................... 35 
9. Statistical Plan .......................................................................................................... 36 
9.1 Determination of Sample Size ................................................................................. 36 
9.2 Analysis Sets ............................................................................................................ 35 
9.2.1 Efficacy Analysis Sets .................................................................................. 35 
9.2.2 Safety Analysis Set ....................................................................................... 35 
10. Data Management and Electronic Systems ......................................................... 36 
Electronic Systems ............................................................................................................ 36 
11. Study Monitoring ................................................................................................... 37 
11.1 Source Document Requirements ............................................................................ 37 
11.2 Case Report Form Requirements ........................................................................... 36 
12. Audits and Inspections .......................................................................................... 37 
13. Ethical and Regulatory Considerations ............................................................... 38 
13.1 Good Clinical Practice Statement .......................................................................... 38 
13.2 Informed Consent................................................................................................... 38 
13.3 Patient Confidentiality and Data Protection .......................................................... 39 
13.4 Institutional Review Board .................................................................................... 39 
14. Protocol Amendments ........................................................................................... 40 
15. Premature Termination of the Study or Close-out of a Site .............................. 40 
15.1 Premature Termination of the Study ...................................................................... 40 
16. Study Documentation ............................................................................................ 41 
16.1 Certification of Accuracy of Data .......................................................................... 41 
16.2 Retention of Records.............................................................................................. 40 
17. References ............................................................................................................... 41 
 
LIST OF TABLES 
Table 1 
Schedule of Events ........................................................................................ 22 
 
 

 
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1. 
INTRODUCTION AND RATIONALE 
1.1 
Introduction 
Macular edema (ME) is a common cause of poor visual outcome following uneventful 
cataract surgery (Tranos PG et al 2004) that has been reported to occur in up to 2% of 
patients (Gallemore RP et al 2006, Powe NR et al 1994, Ursell PG et al 1999); the 
incidence may be as high as 20% when cataract extraction is complicated by posterior 
capsule rupture with vitreous loss or severe iris trauma (Tranos PG et al 2004). Further, it 
is well documented that- macular changes are more likely to occur following cataract 
surgery in diabetic patients, especially those with pre-existing retinopathies, compared 
with nondiabetic patients (Hayashi K et al 2009, Degenring RF et al 2007, Rossetti L et al 
2000, Johnson MW et al 2009). Estimates of the rate of ME development in diabetic 
populations (with or without diabetic retinopathy) vary across studies, and previously 
ranging from 31% to 81% at various time points following cataract extraction (Dowler 
JG et al 1999, Pollack A et al, Krepler K et al 2002, Miyake et al 2002).  
 
Factors involved in the pathogenesis of diabetic ME include chronic hyperglycemia, 
blood-retinal barrier dysfunction, and chronic subclinical inflammation.8 Postsurgical 
inflammation, in particular, is believed to be a major factor in ME that develops 
subsequent to cataract extraction. Prostaglandins contribute substantially to the 
inflammatory processes that result in fluid leakage from perifoveal capillaries into the 
extracellular space of the macular region (Flach AJ 1998).  Postsurgical inflammation, in 
particular, is believed to be a major factor in ME that develops subsequent to cataract 
extraction.  Therefore the use of a pan-VEGF-A inhibitor may prevent the formation of 
macular edema following cataract surgery.    
 
Aflibercept is a recombinantly produced fusion protein consisting of portions of the 
human VEGF receptor extracellular domains fused to the Fc domain of human IgG1 
(Figure 1). Aflibercept is comprised of portions of the extracellular domains of 
2 different VEGF receptors. It contains sequences encoding Ig domain 2 from VEGFR1 
fused to Ig domain 3 from VEGFR2, which in turn is fused to the hinge region of the 

 
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human IgG1 Fc domain. Aflibercept is a dimeric glycoprotein with a protein molecular 
weight of 97 kDa, and contains ~15% glycosylation to give a total molecular weight of 
115 kDa. 
 
Afibercept is approved for the treatment of exudative macular degeneration and macular 
edema secondary to central retinal vein occlusion. 
Figure 1. The Aflibercept Molecule 
 
Figure 1. VEGFR1 and VEGFR2 are related receptors that have 7 Ig domains in the 
extracellular portion and a tyrosine kinase domain intracellularly. Aflibercept contains 
the VEGFR1 Ig2 domain fused to the VEGFR2 Ig3 domain, which is in turn fused to the 
IgG1 Fc. 
 
1.2 
Rationale 
1.2.1 
Rationale for Study Design 
This is a prospective randomized trial of the use of intravitreal aflibercept injection for 
the prevention of diabetic macular edema following cataract surgery in patients with 
preexisting diabetic retinopathy.  This particular population is chosen since macular 
changes are more likely to occur following cataract surgery in diabetic patients, 
especially those with pre-existing retinopathies, compared with non-diabetic patients. A 
previous study in patients with diabetic macular edema (DA VINCI Study Clinical 
Trials.gov# NCT00789477) found that the use of IAI was safe and effective for the 
treatment of diabetic macular edema. Treatment with a single intravitreal aflibercept 
injection will be given at the end of the surgery in half of the patients enrolled, and 

 
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outcomes will be compared to patients who do not receive the drug, and are followed 
only with standard of care.  
 
1.2.2 
Rationale for Dose Selection 
FDA approved dose of 2mg intravitreal aflibercept injection is selected.  Specifically, 
patients will be given 2 mg (0.05 mL or 50 microliters) administered by intravitreal 
injection at the completion of the surgery.  All patients regardless of treatment 
assignment will receive standard of care (SOC) treatment with topical Moxifloxacin 1 
drop four times a day for 1 week and topical Prednisolone acetate 1 drop four times a day 
for two weeks following cataract surgery.   
 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is the incidence and severity of ocular and non-ocular 
adverse events (AEs) and serious AEs.   
 
2.2 
Secondary Objective(s) 
The secondary objectives of the study are – 
 The percentage of patients who develop macular edema within 90 days following 
cataract surgery.  This is defined as any of the following: 
1. ≥30% increase from pre-operative baseline in central subfield macular 
thickness 
2. 2 consecutive measurements (up to 7 days apart) with 
a. BCVA decrease of >5 E-ETDRS letters from the Day 7 
postoperative visit, AND 
b. visual acuity loss due to retinal thickening based on the medical 
judgment of the investigator 
3. Presence of cystoid abnormalities as detected by OCT at any visit 
 Mean change from baseline in best-corrected visual acuity (BCVA) score at Day 
90 

 
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 Changes in macular volume and central retinal thickness from preoperative 
assessment to Day 90  
 Percentage of patients with a best corrected visual acuity (BCVA) decrease of › 5 
E-ETDRS letters from Day 7 postoperative visit 
 Percentage of patients with greater than 15 letters of visual gain at Day 90 
 Percentage of subjects with a loss of 15 letters or more of vision at Day 90 
 Step changes in diabetic retinopathy scale using the E-ETDRS definitions 
 Percentage of patients that are 20/40 or better at Day 90 
 Percentage of patients that are 20/200 or worse at Day 90 
 
3. 
STUDY DESIGN 
3.1 
Study Description and Duration 
This is a prospective randomized trial in patients with a history of non-proliferative or 
inactive proliferative diabetic retinopathy, without clinically significant macular edema 
who are undergoing cataract surgery. Patients will be randomized 1:1 to either intravitreal 
aflibercept injection or sham injection at the time of surgery in a consecutive fashion.   
 
All patients regardless of treatment assignment will receive standard of care (SOC) 
treatment with topical Moxifloxacin 1 drop four times a day for 1 week and topical 
Prednisolone acetate 1 drop four times a day for two weeks following cataract surgery.    
 
One site will enroll 30 patients. Study recruitment is planned to take up to six months 
post IRB approval.  Patients will be enrolled in the study for 3 months post screening and 
enrollment visits. 
 
3.2 
Planned Interim Analysis 
There are no interim analyses planned.   
 

 
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4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS              
4.1 
Number of Patients Planned 
The target enrollment for this study is 30 patients.  Only one eye will be enrolled in the 
study at a time.  If both eyes meet eligibility criteria, the patient may enter the study a 
second time after completing ALL visits for the first eye.  The patient may enroll the 
second eye 90 days after receiving the first study injection provided they meet ALL 
inclusion and NO exclusion criteria.   
4.2 
Study Population 
The study population will consist of approximately 30 patients (15 per treatment group) 
who receive one injection of intravitreal aflibercept injection or Sham injection.  Patients 
must meet all inclusion and exclusion criteria outlined in Section 4.2.1_and Section 4.2.2 
respectively. All patients will undergo a process of informed consent, and sign and date 
an informed consent document before any study-specific procedures are performed. 
 
 The study population will consist of diabetic patients (Type 1 or Type 2) with non-
proliferative or inactive proliferative diabetic retinopathy without clinically significant 
macular edema, 18 years of age and older, of any race and either sex, requiring cataract 
extraction with planned implantation of a posterior chamber intraocular lens into the lens 
capsule. 
 
Patients will be recruited through clinics at the Cole Eye Institute, Cleveland OH.  The 
study will seek approval from the Cleveland Clinic Investigational Review Board (IRB) 
and all study related procedures will be performed in accordance with the Declaration of 
Helsinki and US Code 21 of Federal Regulations.   
 
 
 
 
 
 

 
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4.2.1 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Must be 18 years of age and older, of any race and either sex, who have a cataract, 
and are planning to undergo cataract extraction by phacoemulsification with the 
implantation of a posterior chamber intraocular lens into the lens capsule 
2. History of Type I or Type II diabetes 
3. NPDR (mild, moderate, or severe) or inactive proliferative disease in the study eye 
as defined by the International Clinical Diabetic Retinopathy Disease Severity Scale 
4. Willing and able to comply with clinic visits and study-related procedures 
5. Patients must be able to understand and sign an informed consent that has been 
approved by an Institutional Review Board (IRB) 
6. Central subfield macular thickness ≤ 320 μm in the study eye prior to cataract 
surgery as determined by SD-OCT and confirmed by the Principal Investigator 
7. Absence of clinically significant macular edema (CSME) in the study eye as detected 
by clinical exam 
8. Patients must have visual acuity of 20/20-20/200 (E-ETDRS equivalence is between 
85-30 letters) at the Screening Visit  
 
4.2.2 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Signs of clinically significant vitreomacular traction or clinically significant  
epiretinal membrane in the study eye as detected by the Principal Investigator 
2. Current or previous ocular disease in the study eye that in the opinion of the 
investigator may confound assessment of the macula, the retina, or central vision 
other that diabetic retinopathy 
3. Active proliferative diabetic retinopathy in the study eye 
4. Planned multiple procedures for the study eye during the cataract/IOL implantation 
surgery (e.g., trabeculectomy, corneal transplant) 
5. Patients who have received corneal transplants in the study eye 
6. Patients with current or history of clinically significant chronic or recurrent ocular 
infections or inflammation in the study eye 

 
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7. Patients with a visually nonfunctional fellow eye based upon the assessment by the 
Principal Investigator 
8. Patients who are immunocompromised (e.g., patients receiving chemotherapy 
irradiation therapy, patients with AIDS, leukemia, or cachexia) or patients receiving 
dialysis 
9. Use of medications known to affect the macula, including hydroxychloroquinine 
(Plaquenil) and phenothiozines (e.g., thioridazine [Mellaril], chloropromazine 
[Thorazine]) or supplemental niacin ≥3 grams/day 
10. Use of systemic steroids, NSAIDS, anti-VEGF agents within 7 days prior to surgery 
(through study exit). Daily doses of aspirin, up to 325 mg, will be permitted. 
11. Use of topical ocular NSAIDS and steroids, in the study eye, within 7 days prior to 
surgery 
12. Treatment with intraocular or periocular steroids in the study eye within 3 months 
prior to surgery 
13. Focal photocoagulation for the treatment of diabetic macular edema in the study eye 
within 6 months of the pre-operative Screening Visit (Note: peripheral retina 
treatment for retinal tear or lattice degeneration is permitted) 
14. Intravitreal anti-VEGF treatment in the study eye within 6 months of the pre-
operative baseline visit 
15. Patients with a known hypersensitivity to NSAIDs or steroids or any component of 
the study medication. 
16. Use of a topical ophthalmic prostaglandin (e.g., TRAVATAN, XALATAN) within 4 
days of surgery through study exit 
17. Any concurrent intraocular condition in the study eye that, in the opinion of the 
investigator, could require either medical or surgical intervention during the 90 day 
study period. 
18. Any concurrent ocular condition in the study eye which, in the opinion of the 
investigator, could either increase the risk to the patient beyond what is to be 
expected from standard procedures of intraocular injection, or which otherwise may 
interfere with the injection procedure or with evaluation of efficacy or safety. 
19. Pregnant or breast-feeding women 

 
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20. Sexually active men or women of childbearing potential who are unwilling to 
practice adequate contraception* during the study (adequate contraceptive measures 
include stable use of oral contraceptives or other prescription pharmaceutical 
contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device 
[IUD]; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, 
or jelly, or diaphragm plus contraceptive sponge, foam, or jelly. 
*Contraception is not required for men with documented vasectomy.  
Postmenopausal women must be amenorrheic for at least 12 months in order not to 
be considered of child bearing potential. Pregnancy testing and contraception are 
not required for women with documented hysterectomy or tubal ligation. 
21. Participation in any other clinical study within 30 days of the Baseline examination 
with the exception of patients who are entering their other eye into the study.  Those 
patients may enter sooner than 30 days after the Post-Op Day 90 visit as it will be > 
30 days since the administration of study medicine. 
 
4.3 
Premature Withdrawal from the Study  
A patient has the right to withdraw from the study at any time, for any reason, and 
without repercussion. 
 
The investigator has the right to withdraw a patient from the study in the event of an 
intercurrent illness, adverse event (“AE”), treatment failure, protocol violation, and for 
administrative or other reasons.  An excessive rate of withdrawals would render the study 
uninterpretable; therefore, unnecessary withdrawal of patients will be avoided. 
Should a patient’s (or a patient’s legally authorized guardian or representative) decide to 
withdraw, all efforts will be made to complete and report observations as thoroughly as 
possible.  Early termination procedures will be followed as delineated in section 6.2.5. 
 
4.4 
Replacement of Patients 
Patients prematurely discontinued from the study will not be replaced. 
 

 
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5. 
STUDY TREATMENTS 
Patients will be assigned to treatment with 2 mg intravitreal Aflibercept injection (0.05 
mL or 50 microliters) administered at the time of surgery (post cataract excision) or sham 
injection.  All patients will receive standard of care (SOC) medications in the study eye 
during the 90-day follow up period.  The SOC regimen for all arms will be Ciprofloxacin 
Hydrochloride QID for 1 week following cataract surgery and prednisolone acetate QID 
in the study eye for two weeks following cataract surgery.   
 
5.1 
Dose Modification and Stopping Rules 
5.1.1 
Dose Modification 
Dose modification for an individual patient is not allowed. 
 
5.1.2 
Study Drug Stopping Rules 
If the patient discontinues the study after study drug administration, they will be exited 
from the study and an exit visit will be conducted as outlined in section 6.2.  Any patient 
who discontinues prior to study drug administration will not need to return for an exit 
visit. 
 
5.2 
Method of Treatment Assignment 
Patients will be assigned in a prospective alternating fashion to intravitreal aflibercept 
injection and sham injections.If a patient will be entering both eyes in the study (first eye 
must complete all visits through Post-Op Day 90 before the second eye can be enrolled), 
they will be assigned the next prospective treatment based on the alternating 
Randomization Plan until the entire cohort of 30 patients, with either one or both eyes, is 
achieved.  
 
5.2.1 
Masking 
This is a single masked treatment study and the patients will not be aware of their 
treatment assignment. 
 
 

 
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Emergency Unmasking 
Emergency unmasking of treatment assignment for a patient may be necessary due to a 
medical emergency, a serious adverse event (SAE) that is unexpected and for which a 
causal relationship to study drug cannot be ruled out, or any other significant medical 
event (e.g. pregnancy). 
 
If emergency unmasking is required for a medical emergency: 
 Only the investigator will make the decision to unmask the treatment assignment. 
 Only the patient with the medical emergency will be unmasked. 
 The designated study coordinator at the study site will provide the treatment 
assignment to the investigator. 
 The investigator will notify Regeneron and/or designee that the patient has been 
unmasked. 
 
 
5.3 
Treatment Logistics and Accountability 
5.3.1 
Packaging, Labeling, and Storage 
2.0mg intravitreal aflibercept injection is formulated as a sterile liquid to a final 
concentration of 40 mg/mL aflibercept in 5% sucrose, 10 mM sodium phosphate pH 6.3, 
0.03% polysorbate 20, and 40 mM NaCl. Aflibercept 2.0mg study drug will be supplied 
by Regeneron Pharmaceuticals Inc. in sealed, sterile vials. Vials must be used only once 
(defined as entered with a needle). The volume of injection will be 0.05 mL for the 2 mg 
dose. For study drug in vials, the study drug will be withdrawn using aseptic technique.  
 
Study drug will be shipped to the site via overnight shipping using cold packs to maintain 
a temperature of 2° to 8° C. The Investigator, or an approved representative (e.g. 
pharmacist), will ensure that all study drugs are stored in a secured area, under 
recommended storage conditions and in accordance with applicable regulatory 
requirements. The shipping box is to be opened and stored immediately at the site in a 
refrigerator intended for investigational products at a temperature of 2° to 8°C.  
 

 
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When vials are removed from the refrigerator, the solution should be visually inspected 
and it should have no evidence of turbidity. If particulates, cloudiness, or discoloration 
are visible, the vial must not be used. Exposure of the material to temperatures outside 
these limits, except for warming prior to administration, is not recommended and may 
result in loss of activity. Records of actual storage conditions (i.e. temperature log) at the 
study site must be maintained; and must include a record of the dates, when the 
refrigerator was checked, the initials of person checking, and the temperature. 
 
5.3.2 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2 to 8ºC to the investigator or designee at 
regular intervals or as needed during the study. During site close-out, and following drug 
reconciliation and documentation, all opened and unopened vials of study drug will be 
destroyed or returned to Regeneron Pharmaceuticals, Inc. or designee. 
 
5.3.3 
Treatment Accountability 
All drug accountability records will be kept current. 
The investigator will account for all opened and unopened vials of study drug.  These 
records will contain the dates, quantity, and study medication 
 Date of administration to each patient 
 Disposed of at the site or returned to Regeneron Pharmaceuticals, Inc.  
All accountability records will be made available for inspection by regulatory agency 
inspectors. 
 
5.3.4 
Treatment Compliance 
All drug compliance records will be kept current and will be made available for 
inspection by regulatory agency inspectors.

 
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5.4 
Concomitant Medications and Procedures 
Patients may not receive any medications (approved or investigational) in the study eye 
other than the assigned study treatment (intravitreal Aflibercept injection as specified in 
this protocol, until they have completed the end of study (90 Days) or early treatment 
visit assessments. This includes medications administered locally (eg, IVT, topical, 
juxtascleral or periorbital routes), as well as those administered systemically, with the 
intent of treating the study and/or fellow eye. 
 
If a patient’s fellow (non-study) eye requires treatment with an anti-VEGF agent at study 
entry, or during the patient’s participation in the study, the fellow eye can receive any 
FDA approved anti-VEGF.   If the patient’s fellow eye will be entered into the study 
following completion of all study visits with the first eye, the fellow eye can receive any 
FDA approved anti-VEGF; however, the timeframes listed in the Inclusion and Exclusion 
Criteria must be met prior to re-entering the study with the treated fellow eye. 
 
5.4.1 
Permitted Medications and Procedures 
 Any other medications that are considered necessary for the patient’s welfare, and that 
are not expected to interfere with the evaluation of the study drug, may be given at the 
discretion of the investigator. 
 
5.4.2 
Prohibited Medications and Procedures 
Systemic anti-angiogenic agents will not be permitted during the study. 
 
5.5 
Post-Study Treatment 
Patient must refrain from the use of oral or topical steroids other than the steroid 
prescribed by the physician for 90 days during the course of the study.  Patients must also 
refrain from the use of topical nonsteriodal agents, system nonsteroidal agents, 
intraocular anti-VEGF agents, and systemic anti-VEGF agents for 90 days during the 
course of the study for treatment of the study eye.  All patients regardless of study 
assignment will receive standard of care (SOC) medications in the study eye during the 
90 day follow up period.  The SOC regimen for all arms will be Ciprofloxacin 

 
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21
Hydrochloride QID for 1 week following cataract surgery and prednisolone acetate QID 
in the study eye for two weeks following cataract surgery.   
   
6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
6.1 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
 

 
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22
Table 1 
Schedule of Events 
Study Procedure 
Screening 
(-4 weeks to -2 days) 
 
 
Day 0 
Surgery 
 
Day 1 
(± 1 day) 
 
Day 7 
(± 2 days) 
Day 14 
(-1/+4 days) 
Day 30  (±7 days) 
Day 60 
(±7 days) 
Day 90/ 
Early Exit (± 7 days) 
Visit 
1 
2 
3 
4 
5 
6 
8 
9 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Concomitant Meds  
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
 
 
 
 
 
X 
E-ETDRS BCVA with protocol refraction in Study Eye 
X 
Both Eyes 
 
X 
X 
X 
X 
X 
X 
Intraocular Pressure in Study Eye 
X 
 
X 
X 
X 
X 
X 
X 
SD-OCT for Study Eye 
X 
 
X 
X 
X 
X 
X 
X 
Dilated Fundus Exam in Study Eye 
X 
 
 
 
 
 
 
X 
Wide-field fundus photography for Study Eye 
X 
 
 
 
 
 
 
X 
Slit Lamp in Study Eye 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy test if applies 
X 
 
 
 
 
 
 
 
Hemoglobin A1C value 
X 
 
 
 
 
 
 
 
Administer Study Drug/Sham 
 
X 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 

 
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6.2 
Study Visit Descriptions 
6.2.1 
Screening (Day –4 weeks to Day -2) with the retina specialist  
After the patient has provided informed consent, the following information will be 
collected: 
 Inclusion/exclusion 
 Demographics 
 Medical history and concurrent illnesses 
 Concomitant medications 
The following procedures and assessments will be conducted: 
 Assign a screening number to the patient and record it on the enrollment log. 
 Record the patient’s demographics (birth date, sex, race, and study eye). 
 E-ETDRS visual acuity with protocol refraction. The patient should be manually 
refracted to their best distance acuity by a certified visual acuity examiner using 
trial lenses in both eyes. 
 Measure IOP using Goldmann applanation tonometry (Study eye only). 
 Slit lamp examination: Perform slit-lamp examination to assess corneal edema, 
bulbar conjunctival injection, inflammatory cells and flare (Study eye only). 
 Perform dilated fundus evaluation to assess retina/macula/choroid and optic 
nerve (Study eye only). 
 Retinal exam: NOTE: This step must be performed by a retinal specialist   
a. Assess severity of diabetic retinopathy for eligibility. The confirmation of 
retinopathy will be determined by the retina specialist.   
b. Review exclusion criteria pertinent to posterior segment eligibility. 
 Perform standard wide field fundus photography in the study eye. In cases where 
the physician can see evidence of retinopathy but the fundus photographs are not 
of sufficient quality to accurately determine the severity of retinopathy, the 
patient may be randomized using the physician’s estimate of severity.  
 Spectral Domain OCT evaluation: Measure macular thickness and volume in the 
study eye using SD-OCT performed by a technician.  

 
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24
 Urine pregnancy test. Perform a urine pregnancy test on all females of 
childbearing potential and record the results. If a pregnancy test is not required, 
indicate as not applicable.  
 Perform HbA1c test. 
 Patients must meet all inclusion and exclusion criteria as outlined in Section 
4.2.1 and Section 4.2.2 of this protocol to be eligible for randomization into the 
study.  
 
6.2.1.1 
Day 0 (Surgery Visit) 
The following information will be collected: 
 Concomitant medication changes 
 Adverse Events 
The following procedures and assessments will be conducted by the cataract surgeon: 
 Cataract excision 
The following procedures will be conducted by the Principal Investigator or Designee: 
 Study Drug Administration post cataract excision: record date and time 
 
Record the following surgical information: 
 Surgery start time 
 Surgeon’s name 
 Incision information 
 Type of anesthesia 
 Problems during surgery, if applicable 
 Other surgical procedures, if applicable 
 Intraocular lens information 
 Degree of difficulty of cataract extraction, IOL insertion, and overall surgery 
 Record 
surgery-related 
preoperative 
intraoperative 
and 
immediately 
postoperative medications. 
 Record adverse events. 
 
 

 
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POSTOPERATIVE EXAMINATIONS 
6.2.2. Day 1 (± 1 day) 
All ocular study evaluations refer to the STUDY EYE. 
The following will be performed at the Day 1 Visit by any Investigator: 
 A protocol refraction with E-ETDRS visual acuity assessment. The patient 
should be manually refracted to their best distance acuity by a certified visual 
acuity examiner using trial lenses. 
 Slit-lamp examination 
 Measure IOP using Goldmann applanation tonometry 
 Measure macular thickness and volume using SD-OCT and performed by a 
technician. 
 Record any change in surgery related medications 
 Record any changes in concurrent ocular or non-ocular medications (non-
surgery-related medications) since the first use of the study medication. 
 Record any changes in ocular or non-ocular diseases/conditions since the first 
use of the study medication. 
 Record surgery-related ocular conditions. 
 Record adverse events 
 All patients regardless of treatment assessment will be given 1 bottle of 
Ciprofloxacin Hydrochloride 0.3% (Sandoz) to be instilled into the operative 
eye four times daily for one week.  Patients will also receive 1 bottle of 1% 
Prednisolone acetate (Falcon) to be instilled into the operative eye four times 
daily for two weeks.   
 Schedule patient to return for their next study visit. 
 
 
 
 
 
 

 
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26
6.2.3 Day 7 (± 2 Days), Day 14 (-1 TO +4 Days), Day 30 (± 7 Days), AND Day 60 (± 7 
Days) by any Investigator: 
All ocular study evaluations refer to the STUDY EYE.  
 Assess E-ETDRS best-corrected visual acuity. The patient should be manually 
refracted to their best distance acuity by a certified visual acuity examiner using 
trial lenses. 
 Perform slit-lamp examination and posterior capsular opacification (PCO) 
assessment 
 Measure IOP using Goldmann applanation tonometry. 
 Measure macular thickness and volume using SD-OCT and performed by a 
certified technician. 
 Record any change in surgery related medications. 
 Record any change in concurrent ocular or non-ocular medications (non-surgery-
related medications) since the first use of the study medication. 
 Record any changes in ocular or non-ocular diseases/conditions since the first use 
of the study medication. 
 Record surgery-related ocular conditions 
 Record adverse events. 
 Assess patient for treatment failure. 
o Treatment failure is defined as: 
 .≥ 30% increase from pre-operative baseline in central subfield 
macular thickness  
OR 
 2 consecutive measurements (up to 7 days apart) with BCVA 
decrease of >5 E-ETDRS letters from the Day 7 postoperative 
visit, AND visual acuity loss due to retinal thickening based on the 
medical judgment of the investigator. 
 presence of cystoid abnormalities as detected by OCT at any visit 
o Once treatment failure is determined, the patient will be prescribed 
treatment per the Investigator’s discretion.  The patient will remain in the 
study and complete all future follow-up visits .   

 
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 For patients who have not had their severity of retinopathy confirmed by the 
Reading Center, fundus photographs will be taken on Day 7 and submitted for 
confirmation 
 Schedule patient to return for the next study visit. 
 
6.2.4 
End of Study Visit/Early Termination/ Day 90 (± 7 days) by any 
Investigator 
The following procedures and assessments will be conducted: 
 All ocular study evaluations refer to the STUDY EYE. 
 Record any change in concurrent ocular or non-ocular medications (non-
surgery-related medications) since the first use of the study medication 
 Record any changes in ocular or non-ocular diseases/conditions since the first 
use of the study medication. 
 Assess E-ETDRS best-corrected visual acuity. The patient should be manually 
refracted to their best distance acuity by a certified visual acuity examiner 
using trial lenses 
 Perform slit-lamp examination and PCO assessment (PCO) 
 Measure IOP using Goldmann applanation tonometry 
 Measure macular thickness and volume using SD-OCT performed by a 
technician. 
 Perform dilated fundus evaluation 
 Record any change in surgery related medications. 
 Record surgery-related ocular conditions. 
 Record adverse events. 
 Exit the patient 
 
6.2.5 
Early Termination Visit 
Patients who are withdrawn from the study should be instructed to return to the clinic for 
end of study assessments, as described in section 6.2.4. 
 

 
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6.2.6 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits 
may be necessary, for follow-up of AEs, or for any other reason, as warranted. 
 
6.3 
Study Procedures 
6.3.1 
Efficacy Procedures 
Vision: Visual Acuity Visual function of the study eye and the fellow eye will be 
assessed using the E-ETDRS protocol (The Early Treatment Diabetic Retinopathy Study 
Group, 1985) at 4 meters during the Screening Visit.  Only the Study Eye will be 
assessed during all Post-Op Visits. Visual Acuity examiners must be certified to ensure 
consistent measurement of BCVA.   
 
Spectral Domain Optical Coherence Tomography (OCT): Retinal and lesion 
characteristics will be evaluated using SDOCT on the study eye. At the Screen Visit 
images will be captured and archived. The scanning protocol will consist of fast macular 
thickness maps as well as high definition 6.0 mm linear scans centered on the fovea. OCT 
scans will be recorded by scoring their morphological patterns, and by recording the 
foveal minimum and volumetric analysis for each patient (Cirrus OCT, Humphrey Zeiss 
Inc., San Leandro, CA, software version 5.0).  OCT images will read by the investigator. 
 
Fundus Evaluation and Fundus Photography: The anatomical state of the retinal 
vasculature of the study eye will be evaluated by funduscopic examination. Wide-field 
fundus images will be taken on the designated intervals with the Optos Wide-field 
imaging device.    
 
Intraocular Pressure: Intraocular pressure (IOP) of the study eye will be measured 
using Goldmann Applanation tonometry.  
 

 
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29
6.3.2 
Safety Procedures 
6.3.2.1 
Adverse Event Information Collection 
The investigator (or designee) will record all AEs that occur during the study. AEs will 
be recorded on the AE pages of the CRF (Case report Form) from Screen Visit to Day 90 
or Early Termination Visit. Information on follow-up for AEs is provided in section 7.  
The definition of an AE and SAE, and information on the determination of severity and 
relationship to treatment are provided in section 7. 
 
7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
7.1 
Definitions 
7.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which 
may or may not have a causal relationship with the study drug.  Therefore, an AE is any 
unfavorable and unintended sign (including abnormal laboratory finding), symptom, or 
disease which is temporally associated with the use of a study drug, whether or not 
considered related to the study drug.   
An AE also includes any worsening (i.e. any clinically significant change in frequency 
and/or intensity) of a pre-existing condition that is temporally associated with the use of 
the study drug. 
 
7.1.2 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (e.g. a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate 
risk of death at the time of the event.  This does not include an AE that had it 
occurred in a more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency 
room for longer than 24 hours.  Prolongation of existing hospitalization is defined 
as a hospital stay that is longer than was originally anticipated for the event, or is 

 
PROMISE (Version Dated 31OCT2017) 
 
 
 
 
30
prolonged due to the development of a new AE as determined by the investigator 
or treating physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be 
immediately life-threatening or result in death or hospitalization, but may 
jeopardize the patient or may require intervention to prevent 1 of the other serious 
outcomes listed above (e.g., intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse).  Any 
malignancy (other than basal cell skin cancers) would be considered a medically 
important event. 
 
7.2 
Recording and Reporting Adverse Events 
All AEs will be recorded on the electronic CRF (“eCRF”) and in the patient’s source 
documents.  In addition, all AE’s will be documented on the AE Summary Log and 
reported to the IRB with the Continuing Review Report. 
 
All SAEs, regardless of assessment of causal relationship to study drug will be reported 
to Richard Gans, M.D., Andrew Schachat, M.D., and Regeneron Pharmaceuticals, Inc. 
 
The investigator will promptly report to the IRB and FDA all unanticipated problems 
involving risks to patients.  This includes death from any cause and all SAEs related to 
the use of the study drug.   
7.2.1 
Deaths 
Any AE that results in death is considered an SAE.  Deaths that occur from the time the 
patient signs the informed consent form (“ICF”) until 90 days after dosing will be 
reported to the appropriate IRB, FDA, Richard Gans, M.D., Sponsor, Regeneron 
Pharmaceuticals, Inc.,  and Andrew Schachat, MD. 

 
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31
Any available autopsy reports and relevant medical reports will be sent to Richard Gans, 
M.D. and Regeneron Pharmaceuticals, Inc. as soon as possible.  A MedWatch report will 
be submitted to the FDA in the occurrence of a subject death.   
 
To report an SAE, to Richard Gans, M.D. will be contacted at the following: 
gansr@ccf.org 
Fax: 216-445-2264 
SAE hotline: 216 444 2020 
 
To report an SAE, Regeneron will be contacted at the following: 
Medical.safety@regeneron.com 
Fax: 914-345-7476 
SAE hotline: 914-593-1504 
 
7.2.2 
Pregnancy and Other Events that Require Accelerated Reporting 
The following events will be reported to Richard Gans, M.D. within 24 hours of learning 
of the event: 
Overdose:  Accidental or intentional overdose of the study drug or concomitant 
medication, whether or not it is considered an AE. 
Pregnancy:  Although it is not considered an AE, the investigator will report to Richard 
Gans, M.D., any pregnancy occurring in a female patient or female partner of a male 
patient, during the study or within 30 days following the last dose of study drug.  The 
investigator will follow the pregnancy until delivery, or longer.  If the pregnancy 
continues to term (delivery), the health of the infant will also be reported to Richard Gans 
M.D. and Regeneron Pharmaceuticals, Inc. 
 
 
 
To report an SAE, to Richard Gans, M.D. will be contacted at the following: 
gansr@ccf.org 
Fax: 216-445-2264 

 
PROMISE (Version Dated 31OCT2017) 
 
 
 
 
32
SAE hotline: 216 444 2020 
 
To report an SAE, Regeneron will be contacted at the following: 
Medical.safety@regeneron.com 
Fax: 914-345-7476 
SAE hotline: 914-593-1504 
 
7.2.3 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study will be reported to Richard 
Gans, M.D., Andrew Schachat, M.D.,and Regeneron Pharmaceuticals, Inc. within 30 
days.  
 
To report an SAE,  Richard Gans, M.D. will be contacted at the following: 
gansr@ccf.org 
Fax: 216-445-2264 
SAE hotline: 216 444 2020 
 
To report an SAE, Regeneron will be contacted at the following: 
Medical.safety@regeneron.com 
Fax: 914-345-7476 
SAE hotline: 914-593-1504 
 
7.2.4 
Abnormal Vital Signs Results 
The criteria for determining whether an abnormal objective test finding will be reported 
as an AE are as follows: 
 the test result is associated with accompanying symptoms, and/or 
 the test result requires additional diagnostic testing or medical/surgical 
intervention, and/or 
 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy. 

 
PROMISE (Version Dated 31OCT2017) 
 
 
 
 
33
Repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not 
require reporting as an AE. 
 
7.2.5 
Follow-up 
Adverse event information will be collected until the end of study visit, or the early 
termination visit, if the patient withdraws consent. 
 
The investigator must make every effort to obtain follow-up information on the outcome 
of any SAE until the event is considered chronic and/or stable. 
 
7.3 
Evaluation of Severity and Causality 
7.3.1 
Evaluation of Severity 
The severity of an AE will be graded by the investigator using a 3–point scale (mild, 
moderate, or severe) and reported in detail as indicated on the eCRF and/or SAE form, as 
appropriate. 
 Mild:  Does not interfere in a significant manner with the patient’s normal 
functioning level.  It may be an annoyance.  Prescription drugs are not ordinarily 
needed for relief of symptoms, but may be given because of personality of the 
patient. 
 Moderate:  Produces some impairment of functioning but is not hazardous to 
health.  It is uncomfortable or an embarrassment.  Treatment for symptom may be 
needed. 
Severe:  Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the patient’s health.  Treatment for symptom may be given 
and/or patient hospitalized. 
 

 
PROMISE (Version Dated 31OCT2017) 
 
 
 
 
34
The severity of an AE will be graded by the investigator using a 3–point scale 
(mild, moderate, or severe) and reported in detail as indicated on the CRF and/or 
SAE form, as appropriate. 
Mild:  Mild AE (minor; no specific medical intervention; asymptomatic 
laboratory findings only, radiographic findings only; marginal clinical relevance). 
Moderate: Moderate AE (minimal intervention; local intervention; noninvasive 
intervention [packing, cautery]). 
Severe: Severe and undesirable AE (significant symptoms requiring 
hospitalization or invasive intervention; transfusion; elective interventional 
radiological procedure; therapeutic endoscopy or operation). 
Life–threatening: Life-threatening or disabling AE (complicated by acute, life-
threatening metabolic or cardiovascular complications such as circulatory failure, 
hemorrhage, sepsis. Life-threatening physiologic consequences; need for 
intensive care or emergent invasive procedure; emergent interventional 
radiological procedure, therapeutic endoscopy or operation). 
Death: Death associated with an AE. 
 
7.3.2 
Evaluation of Causality 
The relationship to treatment will be determined by the investigator and reported on the 
eCRF and/or SAE form, as appropriate.  The following terms will be used: 
Not Related:  likely or clearly due to causes other than the study drug. 
Related:  possibly, probably, or definitely related to the study drug. 
 
8. 
STUDY VARIABLES 
8.1 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (e.g. age, race, sex, etc.), 
disease characteristics including medical history, and medication history for each patient. 
 
 
 

 
PROMISE (Version Dated 31OCT2017) 
 
 
 
 
35
8.2 
Primary and Secondary Endpoints 
Primary Endpoint 
 The incidence and severity of ocular and non-ocular adverse events (AEs) and 
serious AEs. 
 
Secondary Endpoints -   
 The primary endpoint of the study is the percentage of patients who develop 
macular edema within 90 days following cataract surgery.  This is defined as any 
of the following: 
o ≥30% increase from pre-operative baseline in central subfield macular 
thickness 
o 2 consecutive measurements (up to 7 days apart) with 
 BCVA decrease of >5 E-ETDRS letters from the Day 7 
postoperative visit, AND 
 Visual acuity loss due to retinal thickening based on the medical 
judgment of the investigator 
o Presence of cystoid abnormalities as detected by OCT at any visit 
o Mean change from baseline in best-corrected visual acuity (BCVA) score 
at Day 90 
o Changes in macular volume and central retinal thickness from 
preoperative assessment to Day 90  
o Percentage of patients with a best corrected visual acuity (BCVA) 
decrease of › 5 E-ETDRS letters from Day 7 postoperative visit 
o Percentage of patients with greater than 15 letters of visual gain at Day 90 
o Percentage of subjects with a loss of 15 letters or more of vision at Day 90 
o Step changes in diabetic retinopathy scale using the E-ETDRS definitions 
o Percentage of patients that are 20/40 or better at Day 90 
o Percentage of patients that are 20/200 or worse at Day 90 
 
 

 
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36
9. 
STATISTICAL PLAN 
9.1 
Determination of Sample Size 
Based on previous studies performed within the same patient cohort, assuming the study 
would have at least 80% power, there would be the ability to detect a difference of 
approximately 45%-50% (i.e. 50%  vs. 5%) between groups. With 40 total patients you 
would be able to detect a difference of at least 40%-45% (45% vs. 5%).   
 
9.2 
Analysis Sets 
9.2.1 
Efficacy Analysis Sets 
Demographic and baseline characteristics will be summarized descriptively by treatment 
group for all patients.  Continuous variables will be summarized with mean, median, 
standard deviation, minimum, and maximum.  Categorical variables will be summarized 
with frequency and percentage 
 
9.2.2 
Safety Analysis Set 
Adverse events from all enrolled patients will be utilized to summarize safety 
data. 
 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation, cleaning, correcting, releasing) will be maintained and stored 
at the study site. 
 
The CRF data for this study will be collected with an Electronic Data Capture ("EDC") 
tool [ImageIQ]. 
 
Electronic Systems 
Electronic systems used to process and/or collect data in this study will include the 
following: 
 [Epic and ImageIQ] – EDC system. 

 
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37
 Statistical Analysis Software (“SAS”) – statistical review and analysis. 
 
11. 
STUDY MONITORING 
11.1 
Source Document Requirements 
Investigator will prepare and maintain adequate and accurate patient records (source 
documents). 
 
The investigator will keep all source documents on file with the CRF.  Case report forms 
and source documents will be available at all times for inspection by authorized 
representatives of the regulatory authorities. 
 
11.2 
Case Report Form Requirements 
An eCRF for each patient enrolled in the study will be completed and signed by the study 
investigator or authorized designee. Study data obtained in the course of the clinical study 
will be recorded on eCRFs by trained site personnel.  ImageIQ will serve as the eCRF 
systems. An eCRF will be completed for each and every patient enrolled in the study.  
After review of the clinical data for each patient, the investigator will provide an 
electronic signature.  A copy of each eCRF page will be retained by the investigator as 
part of the study record and will be available at all times for inspection by authorized 
representatives of the regulatory authorities. 
 
Corrections to the eCRF will be entered in the eCRF by the investigator or an authorized 
designee.  All changes, including date and person performing corrections, will be 
available via the audit trail, which is part of the system.  For corrections made via data 
queries, a reason for any alteration will be provided. 
 
12. 
AUDITS AND INSPECTIONS 
This study may be patient to a quality assurance audit or inspection by the regulatory 
authorities.  Should this occur, the investigator will be responsible for: 
 Informing Regeneron of a planned inspection by the authorities as soon as 
notification is received 

 
PROMISE (Version Dated 31OCT2017) 
 
 
 
 
38
 Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
 Communicating any information arising from inspection by the regulatory 
authorities to the Regeneron immediately 
 Taking all appropriate measures requested by the regulatory authorities to resolve 
the problems found during the audit or inspection 
 
Documents patient to audit or inspection include but are not limited to all source 
documents, eCRFs, medical records, correspondence, ICFs, IRB files, documentation of 
certification and quality control of supporting laboratories, and records relevant to the 
study maintained in any supporting pharmacy facilities.  Conditions of study material 
storage are also patient to inspection.   
 
In all instances, the confidentiality of the data will be respected. 
 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 
Good Clinical Practice Statement 
It is the responsibility of the investigator(s) to ensure that this clinical study will be 
conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, and that are consistent with the ICH guidelines for Good Clinical 
Practice (GCP) and applicable regulatory requirements. 
 
13.2 
Informed Consent 
The principles of informed consent are described in ICH Guidelines for GCP. 
Regeneron will have the right to review and comment on the informed consent form. 
 
It is the responsibility of the investigator or designee (if acceptable by local regulations) 
to obtain written informed consent from each patient prior to his/her participation in the 
study and after the aims, methods, objectives, and potential hazards of the study have 
been explained to the patient in language that he/she can understand.  The ICF will be 

 
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39
signed and dated by the patient and by the investigator or authorized designee who 
reviewed the ICF with the patient.   
 
Patients who can write but cannot read will have the ICF read to them before signing and 
dating the ICF. 
 
Patients who can understand but who can neither write nor read will have the ICF read to 
them in presence of an impartial witness, who will sign and date the ICF to confirm that 
informed consent was given. 
 
The original ICF will be retained by the investigator as part of the patient's study record, 
and a copy of the signed ICF will be given to the patient. 
 
If new safety information results in significant changes in the risk/benefit assessment, the 
ICF will be reviewed and updated appropriately.  All study patients will be informed of 
the new information and provide their written consent if they wish to continue in the 
study.  The original signed revised ICF will be maintained in the patient’s study record 
and a copy will be given to the patient. 
 
13.3 
Patient Confidentiality and Data Protection 
The investigator will take all appropriate measures to ensure that the anonymity of each 
study patient will be maintained.   
 
The patient's and investigator's personal data will be treated in compliance with all 
applicable laws and regulations.   
 
13.4 
Institutional Review Board  
An appropriately constituted IRB/IEC, as described in ICH Guidelines for GCP, will 
review and approve:  
 The protocol, ICF, and any other materials to be provided to the patients 
(e.g. advertising) before any patient may be enrolled in the study  

 
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40
 Any amendment or modification to the study protocol or ICF before 
implementation, unless the change is necessary to eliminate an immediate hazard 
to the patients, in which case the IRB will be informed as soon as possible  
Ongoing studies will be reviewed by the IRB/EC on an annual basis or at intervals 
appropriate to the degree of risk.  
 
In addition, the IRB will be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
 
A copy of the IRB approval letter will be sent to Regeneron prior to shipment of drug 
supplies to the investigator.  The approval letter will include the study number and title, 
the documents reviewed, and the date of the review. 
 
Records of the IRB review and approval of all study documents (including approval of 
ongoing studies) will be kept on file by the investigator. 
 
14. 
PROTOCOL AMENDMENTS 
The investigator will not implement a change in the design or operation of the protocol or 
ICF without an IRB-approved amendment. 
 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A SITE 
15.1 
Premature Termination of the Study 
The investigator will notify Regeneron of a desire to close-out a site in writing, providing 
approximately 30 days’ notice.  The final decision will be made through mutual 
agreement with Regeneron.  Both parties will arrange the close-out procedures after 
review and consultation. 
 
In all cases, the appropriate IRB and Health Authorities will be informed according to 
applicable regulatory requirements, and adequate consideration will be given to the 
protection of the patients’ interests. 
 

 
PROMISE (Version Dated 31OCT2017) 
 
 
 
 
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16. 
STUDY DOCUMENTATION 
16.1 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRFs will be 
signed by the investigator.  This certification form accompanies each set of CRFs.  
 
16.2 
Retention of Records 
The investigator will retain all essential study documents, including ICFs, source 
documents, CRFs, and drug accountability records for at least 5 years following the 
completion or discontinuation of the study, or longer if a longer period is required by 
relevant regulatory authorities.  Records will be destroyed in a manner that ensures 
confidentiality. 

 
PROMISE (Version Dated 31OCT2017) 
 
 
 
 
42
 
17. 
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