Clinical trial NCT02363621
Conditions: Diabetic Macular Edema
Sponsor: Arshad Khanani
Start date: 2015-01-01; Completion date: 2017-10-01
Enrollment: 101 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to compare the post injection inflammation and pain seen after intravitreal injections of ranibizumab 0.3mg and aflibercept 2.0mg in patients with DME.

The investigators will be evaluating patients (1-7 days) post injections for:

1\. Intraocular inflammation (defined as anterior chamber and/or vitreous cells 2. Pain (as measured on a standardized pain scale).

Detailed description:
This is an open-label, Phase II study of post injection pain and inflammation after intravitreally administered ranibizumab and aflibercept in 100 subjects with Diabetic Macular Edema. Treatment naïve and experienced patients will be enrolled. Treatment experienced patients with history of anti-vegf injections will be eligible as long as they have not received any intravitreal injection in the 3 months prior to the study visit. Patients will be randomized to receive either Lucentis 0.3 mg or Eylea 2.0 mg, and followed for a week. A non-injecting masked physician who is blinded to the treatment drug will evaluate the patient at baseline before the injection and then within 1-2 days and 5-7 days after the injection for anterior chamber and vitreous cells using slit lamp examination and indirect ophthalmoscopy. Pain will also be recorded at these visits using a standardized pain scale.

Consented, enrolled subjects will receive open-label intravitreal injection of either 0.3 mg ranibizumab or 2.0 mg aflibercept. A standard intravitreal injection protocol will be followed. Patients will be revaluated at baseline, 1-2 days and 5-7 days post injections. A non-injecting physician will evaluate the patients for anterior chamber and vitreous inflammation; this physician will be blinded about the specific treatment. Anterior chamber inflammation is described as any cell or flare in the anterior chamber. These will be evaluated using Standardization of Uveitis Nomenculature (SUN) working group classifications. Pain score will be evaluated using a Numerical Rating Scale.

Arms: arm 1: Intravitreal injection of Ranibizumab 0.3 mg once arm 2: Intravitreal Aflibercept 2.0 mg once
Interventions: intervention 1: Ranibizumab 0.3 mg intervention 2: Aflibercept 2.0 mg
Intervention descriptions: intervention 1: Ranibizumab 0.3 mg Patient will receive intravitreal injection of Ranibizumab 0.3 mg intervention 2: Patient will receive intravitreal injection of Aflibercept 2.0 mg

Protocol documents:
Prot_SAP_000.pdf: 
Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
 
PROTOCOL 
STUDY TITLE: 
Evaluation of Inflammation and Pain Post 
Injection of Ranibizumab  vs. Aflibercept in 
Patients with Diabetic Macular Edema 
Phase II 
STUDY DRUG 
Recombinant humanized anti-VEGF 
monoclonal antibody fragment (rhuFab V2 
[ranibizumab]) 
Recombinant fusion protein consisting of 
portions of human VEGF receptors 1 and 2 
extracellular domains fused to the Fc portion of 
human IgG1 (aflibercept)  
SPONSOR 
Sierra Eye Associates 
950 Ryland Street, Reno, Nevada, 89511 
INVESTIGATOR 
Arshad Khanani M.D. 
SUB-
INVESTIGATORS 
Gregory Cohen M.D. 
DATE FINAL: 
14-Dec-2014 
AMENDMENT : 


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TABLE OF CONTENTS 
 
                         Page:         
1. 
BACKGROUND ...........................................................................................  
 
1.1 
Pathophysiology ................................................................................  
 
1.2 
Treatment ..........................................................................................  
 
1.3 
Ranibizumab and Aflibercept ............................................................  
1.4 
Nonclinical Experience with Ranibizumab .........................................  
 
1.4.1 
Nonclinical Pharmacokinetics ..............................................  
 
1.4.2 
Nonclinical Toxicology .........................................................  
 
1.4.3 
Stability Studies ...................................................................  
 
1.5 
Clinical Experience with Ranibizumab ...............................................  
1.6      Clinical Experience with Aflibercept ..................................................  
2. 
OBJECTIVES ...............................................................................................  
 
2.1 
Primary Objective    ……………………………………………………… 
 
2.2 
Secondary Objective …………………………………………………….   
3. 
STUDY DESIGN ..........................................................................................  
 
3.1 
Description of the Study ....................................................................  
 
3.2 
Rationale for Study Design ................................................................  
 
3.3 
Outcome Measures ...........................................................................  
 
3.3.1 
Primary Outcome Measures ................................................  
 
3.3.2 
Secondary Outcome Measures ...........................................  
 
3.4 
Safety Plan ........................................................................................  
 
3.5 
Compliance with Laws and Regulations ............................................  
4. 
MATERIALS AND METHODS .....................................................................  
 
4.1 
Subjects ............................................................................................  
 
4.1.1 
Subject Selection .................................................................  
 


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TABLE OF CONTENTS (cont’d) 
 
                   Page 
4. 
MATERIALS AND METHODS (cont’d) 
4.1.2 
Inclusion Criteria ..................................................................  
 
4.1.3 
Exclusion Criteria .................................................................  
 
4.2 
Method of Treatment Assignment ………………………………………    
4.3 
Study Treatment ................................................................................  
 
4.3.1 
Formulation ..........................................................................  
 
4.3.2 
Dosage, Administration, and Storage ..................................  
 
4.4 
Concomitant and Excluded Therapies ...............................................  
 
4.5 
Study Assessments ...........................................................................  
4.5.1 
Assessments during the Treatment Period ..........................  
 
4.5.2 
Early Termination Assessments...........................................  
 
4.6  
Subject Discontinuation .....................................................................  
 
4.7  
Study Discontinuation ........................................................................  
4.8  
Statistical Methods ……………………………………………………….    
 
4.8.1      Analysis of the Conduct of the Study ...................................  
 
4.8.2 
Safety Analyses ...................................................................  
4.8.3 
Efficacy Analyses .................................................................  
 
4.8.4 
Missing Data ........................................................................  
 
4.8.5 
Interim Analyses ……………………………………………….. 
 
4.9 
Data Quality Assurance …………………………………………………. 
5. 
ASSESSMENT OF SAFETY ........................................................................  
 
5.1 
Adverse Events .................................................................................  
 
5.2 
Serious Adverse Events ....................................................................  
5.3 
Methods and Timing for Assessing and Recording Safety Variables  
5.4 
Evaluations ........................................................................................  
5.5 
Vital Signs .........................................................................................  
5.6 
Procedures for Eliciting, Recording, and Reporting Adverse Events .  
 
5.6.1 
Eliciting Adverse Events ......................................................  
 
5.6.2 
Specific Instructions for Recording Adverse Events.............  
 
5.6.3 
Med Watch 3500A Reporting Guidelines …………………… 
 
5.6.4 
Follow-up Information ..........................................................  
 
5.6.5 
Additional Reporting Requirements for IND Holders 
 
 
5.6.6  
Safety Reporting Fax Cover Sheet ......................................  
 
 


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TABLE OF CONTENTS (cont’d) 
 
                   Page 
 
 
6. 
INVESTIGATOR REQUIREMENTS ............................................................  
 
6.1 
Study Initiation ...................................................................................  
 
6.2 
Study Completion ..............................................................................  
 
6.3 
Informed Consent Form ....................................................................  
 
6.4 
Institutional Review Board or Ethics Committee Approval .................  
 
6.5 
Case Report Forms ...........................................................................  
 
6.6 
Study Drug Accountability……………………………………………….. 
 
6.7 
Disclosure of Data .............................................................................  
  
6.8 
Retention of Records .........................................................................  
 
 
6.9  
Study Close-Out ................................................................................  
 
REFERENCES ....................................................................................................  
 
 
 
APPENDICES 
Appendix A: 
Study Flowchart………………………………………………………. 
    
Appendix B: 
Pre-Injection Procedures for All Subjects………………………….. 
Appendix C: 
 Analysis of Similar Events …………………………………………... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
BACKGROUND 
1.1 
PATHOPHYSIOLOGY 
 
Diabetic Macular edema (DME) is caused by accumulation of fluid and 
exudates in the macula. It is mediated by the production of VEGF and other 
growth factors in response to ischemia. In patients with diabetes for over 10 
years, the prevalence of DME is estimated at one in four in type 2 diabetics 
and one in five people with type 1 diabetics. 
 
1.2 
TREATMENT  
There are several options available for the treatment of Diabetic Macular Edema 
including focal laser, grid laser and ozurdex injection. Lucentis 0.3mg and Eylea 
2.0mg are also FDA approved for DME 
 
1.3 
RANIBIZUMAB AND AFLIBERCEPT  
Ranibizumab 0.3mg is FDA approved treatment and is available to patients 
with Diabetic Macular Edema. 
Ranibizumab is a recombinant humanized monocolonal antibody that binds to 
human vascular endothelial growth factor A (VEGF-A). The binding of 
Ranibizumab to VEGF-A inhibits the interaction of VEGF-A with its receptors 
on the surface of the endothelial cells, resulting in reduced vascular leakage 
and new blood vessel proliferation. 
Aflibercept 2.0mg is  FDA  approved for DME . Aflibercept acts as a soluble 
decoy receptor that binds to human vascular endothelial growth factor A 
(VEGF-A) and placental growth factor (PIGF). VEGF-A and PIGF act as 
mitogenic, chemotactic, and vascular permeability factors for endothelial cells. 
Inhibiting these factors with Aflibercept results in decreased neovascularization 
as well as vascular permeability. 
 


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1.4 
NONCLINICAL EXPERIENCE WITH RANIBIZUMAB 
1.4.1 Nonclinical Pharmacokinetics 
The pharmacokinetics of ranibizumab have been investigated in rabbits and 
cynomolgus monkeys following intravitreal and intravenous administration.  In 
both species, following intravitreal administration, ranibizumab was cleared 
from the vitreous humor with a half-life of 2–3 days.  Following single 
intravitreal administration to cynomolgus monkeys, retinal concentrations of 
ranibizumab were approximately one-third of vitreous concentrations and 
declined in parallel with vitreous concentrations. In humans, the intravitreal 
half-life of ranibizumab is estimated to be 9 days.  Repeated intravitreal 
injections of ranibizumab can lead to detectable antibodies in serum in rabbits 
and cynomolgus monkeys. 
 
1.4.2 Nonclinical Toxicology 
A series of nonclinical studies of ranibizumab administered by intravitreal 
injection to cynomolgus monkeys have been performed (details regarding 
study design and results can be found in the Investigator Brochure). 
 
1.4.3 Nonclinical Data Supporting the Anti-Edema Activity of Ranibizumab 
In Studies 01-401E-1757 and 01-401G-1757, the effect of ranibizumab on 
vascular leakage was explored using a modified Miles assay in the guinea pig.  
Ranibizumab demonstrated a concentration-dependent effect of blunting the 
vascular permeability induced by VEGF.  These results are consistent with the 
decrease in retinal vascular permeability as observed on optical coherence 
tomography (OCT) and fluorescein angiography in AMD and diabetic macular 
edema studies and further support the rationale for the use of ranibizumab in 
CRVO and BRVO, in which vascular permeability plays a significant role in the 
pathology   
 
1.5 
CLINICAL EXPERIENCE WITH RANIBIZUMAB 
The safety and efficacy of LUCENTIS were assessed in two randomized, double-
masked, 3-year studies in patients with DME. The studies were sham-controlled 
through Month 24. Patient age ranged from 21 to 91 years, with a mean age of 62 


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years. A total of 759 patients (LUCENTIS 0.3 mg, 250 patients; LUCENTIS 0.5 mg, 
252 patients; sham, 257 patients) were enrolled, with 582 (77%) completing through 
Month 36.  
In Studies DME-1 and DME-2, patients received monthly LUCENTIS 0.3 mg or 0.5 mg 
intravitreal injections or monthly sham injections during the 24-month controlled 
treatment period. From Months 25 through 36, patients who previously received sham 
were eligible to receive monthly LUCENTIS 0.5 mg and patients originally randomized 
to monthly LUCENTIS 0.3 mg or 0.5 mg continued to receive their assigned dose. All 
patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 
24-month treatment period or panretinal photocoagulation (PRP) as needed. Through 
Month 24, macular focal/grid laser treatment was administered in 94 of 250 (38%) 
patients treated with LUCENTIS 0.3 mg and 185 of 257 (72%) patients treated with 
sham; PRP was administered in 2 of 250 (1%) patients treated with LUCENTIS 0.3 mg 
and 30 of 257 (12%) patients treated with sham.  
          In a pooled analysis of Studies DME-1 and DME-2, the ATE rate at 2 years was 7.2% 
(18 of 250) with 0.5 mg LUCENTIS, 5.6% (14 of 250) with 0.3 mg LUCENTIS, and 
5.2% (13 of 250) with control. The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 
mg LUCENTIS, 1.2% (3 of 250) with 0.3 mg LUCENTIS, and 1.6% (4 of 250) with 
control. At 3 years, the ATE rate was 10.4% (26 of 249) with 0.5 mg LUCENTIS and 
10.8% (27 of 250) with 0.3 mg LUCENTIS; the stroke rate was 4.8% (12 of 249) with 
0.5 mg LUCENTIS and 2.0% (5 of 250) with 0.3 mg LUCENTIS. 
 
1.6      CLINICAL EXPERIENCE WITH AFLIBERCEPT FOR DME 
 
          Aflibercept 2.0mg injection has been  FDA approved for DME after the completion of 
VIVID-DME and VISTA-DME clinical trials. The VIVID-DME and VISTA-DME trials 
were similarly designed, randomized, double-masked, active control trials to evaluate 
the safety and efficacy of EYLEA in patients with DME.  Patients in both trials were 
randomized to receive either EYLEA 2 milligrams (mg) monthly, EYLEA 2 mg every 
two months (after 5 initial monthly injections), or the comparator treatment of laser 


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photocoagulation.    
           In the VIVID-DME trial, after one year patients receiving EYLEA 2 mg monthly had a 
mean change from baseline in BCVA of 10.5 letters (p < 0.0001 compared to laser) 
and patients receiving EYLEA 2 mg every other month (after 5 initial monthly 
injections) had a mean change from baseline in BCVA of 10.7 letters (p < 0.0001 
compared to laser), compared to patients receiving laser photocoagulation who had a 
mean change from baseline in BCVA of 1.2 letters. 
           In the VISTA-DME trial, after one year patients receiving EYLEA 2 mg monthly had a 
mean change from baseline in best-corrected visual acuity (BCVA) of 12.5 letters (p < 
0.0001 compared to laser) and patients receiving EYLEA 2 mg every other month 
(after 5 initial monthly injections) had a mean change from baseline in BCVA of 10.7 
letters (p < 0.0001 compared to laser), compared to patients receiving laser 
photocoagulation who had a mean change from baseline in BCVA of 0.2 letters.  
          In these trials, EYLEA was generally well tolerated with a similar overall incidence of 
adverse events (AEs), ocular serious AEs, and non-ocular serious AEs across the 
treatment groups and the laser control group.  Arterial thromboembolic events as 
defined by the Anti-Platelet Trialists' Collaboration (non-fatal stroke, non-fatal 
myocardial infarction, and vascular death) also occurred at similar rates across the 
treatment groups and the laser control group.  AEs were typical of those seen in other 
studies in patients with diabetes receiving intravitreal anti-VEGF therapy.  The most 
frequent ocular treatment emergent AEs (TEAEs) observed in the VIVID-DME and 
VISTA-DME trials included conjunctival hemorrhage, eye pain, and vitreous floaters. 
 The most frequent non-ocular TEAEs included hypertension and nasopharyngitis, 
which occurred with similar frequency in the treatment groups and the laser control 
group.  
 
 
 
 
 
 
 


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2. 
OBJECTIVES 
This study is designed to compare the post injection inflammation and pain seen after 
intravitreal injections of ranibizumab 0.3mg and aflibercept 2.0mg in patients with 
DME. 
We will be evaluating patients (1-7 days) post injections for: 
           1. Intraocular inflammation (defined as anterior chamber and/or vitreous cells)  
 2. Pain (as measured on a standardized pain scale). 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an open-label, Phase II study of post injection pain and inflammation 
after intravitreally administered ranibizumab and aflibercept in 100 subjects 
with Diabetic Macular Edema. Treatment naïve and experienced patients will 
be enrolled. Treatment experienced patients with history of anti-vegf injections 
will be eligible as long as they have not received any intravitreal injection in the 
3 months prior to the study visit. Patients will be randomized to receive either 
Lucentis 0.3 mg or Eylea 2.0 mg, and followed for a week.  A non-injecting 
masked physician who is blinded to the treatment drug will evaluate the patient 
at baseline before the injection and then within 1-2 days and 5-7 days after the 
injection for anterior chamber and vitreous cells. Pain will also be recorded at 
these visits using a standardized pain scale. 
Consented, enrolled subjects will receive open-label intravitreal injection of 
either 0.3 mg ranibizumab or 2.0 mg aflibercept. A standard intravitreal 
injection protocol will be followed. Patients will be revaluated at baseline, 1-2 
days and 5-7 days post injections.  A non-injecting physician will evaluate the 
patients for anterior chamber and vitreous inflammation; this physician will be 
blinded about the specific treatment.  Anterior chamber inflammation is 
described as any cell or flare in the anterior chamber. These will be evaluated 
using Standardization of Uveitis Nomenculature (SUN)6 working group 
classifications (see Appendix D). Pain score will be evaluated using a 


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Numerical Rating Scale. (See Appendix E)  Each patient will have a standard 
script verbally read to them at their visit, and asked to rate their pain based on 
this scale.  Their answers will be captured in a CRF.  Patients will also be 
contacted via telephone by the study coordinator between the first 2 visits to 
inquire about pain, and will go through this same pain scale over the phone, 
using the same script. If the patient complains of increased pain score since 
visit #1, another visit will be initiated prior to the scheduled visit #2 
We plan to enroll 100 patients in the study. We plan to recruit 8 patients per 
month and finish the study in 13 months. 
3.2 
RATIONALE FOR STUDY DESIGN 
Patients will be injected with ranibizumab 0.3mg  and aflibercept 2.0mg. Almost all 
complaints after intravitreal injections occur during the first week post injection, 
especially within the first 48 hours. Therefore, we plan to evaluate patients 1-2 days 
post injection and 5-7 days post injection1,2,3,4,5.   
 
 
3.3 
OUTCOME MEASURES 
3.3.1 Primary Outcome Measures 
1. Evidence of anterior chamber and vitreous inflammation at visit #1 and #2 
compared with baseline 
 
3.3.2 Secondary Outcome Measures 
 
1. Pain post injection as measured on a standardized pain scale at visit #1 
and #2. compared with baseline 
 
3.4 
SAFETY PLAN 
The safety assessments to be conducted for this study are listed in Section 4.5 
and Appendix A. 
Patients are treated with the suggested study medications on a daily basis in 
our clinic, routine safety protocols will be used to notify patients about the 
adverse reactions to the suggested medications. 
 


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3.5 
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), and local ethical and 
legal requirements. 
 
4. 
MATERIALS AND METHODS 
4.1 
SUBJECTS 
4.1.1 Subject Selection 
 
100 subjects with Diabetic Macular Edema from 1 site in the United States will be 
enrolled.   Eligible subjects will be administered and provided with a copy of an 
informed consent form.  (See Appendix A, the study flow chart, for screening 
assessments.) 
 
 
4.1.2 Inclusion Criteria 
Subjects will be eligible if the following criteria are met:  
• Ability to provide written informed consent and comply with study 
assessments for the full duration of the study 
• Age > 21 years 
• Exam and OCT confirming Diabetic Macular Edema 
• Visual Acuity of 20/400 or better 
• No history of post injection pain or inflammation in the past 
 
 
 
 
 
 
4.1.3 Exclusion Criteria 
 
Subjects who meet any of the following criteria will be excluded from this study 
 
• History of Endophthalmitis in either eye 
• Current inflammation in either eye 
• Uncontrolled or symptomatic Dry Eye Syndrome 
• Intravitreal injection less than 3 months ago 
• History of Anterior or Posterior Uveitis 
• History of post injection pain with prior treatments 
• Recent thromboembolic event (<3 months) 
• Pregnancy (positive pregnancy test) or lactation   


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• Premenopausal women not using adequate contraception.  The       
following are considered effective means of contraception:  
surgical sterilization or use of oral contraceptives, barrier 
contraception with either a condom or diaphragm in conjunction 
with spermicidal gel, an IUD, or contraceptive hormone implant 
or patch. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
Patients will be randomly assigned to either ranibizumab or aflibercept 
treatment group. The physician evaluating for anterior chamber and vitreous 
inflammation will be blinded about the treatment given to the patient. The 
investigator and the patients will be aware of the treatment given. Patients will 
be randomized by drawing the medicine name from an envelope. 
 
4.3 
STUDY TREATMENT 
4.3.1 Formulation 
Ranibizumab is formulated as a sterile solution aseptically filled in a sterile,3-mL 
stoppered glass vial. Each vial is designed to give 0.05 ml with resulting 0.3mg dose. 
Each vial contains no preservative and is suitable for single use only. 
Aflibercept is formulated as a sterile solution in a single-use, glass vial designed to 
provide 0.05 mL of 40 mg/mL solution for intravitreal injection. 
Further details and molecule characterization will be included in the Investigator 
Brochure. 
 
4.3.2 Dosage, Administration, and Storage 
a. Dosage 
Ranibizumab 0.3mg and Aflibercept 2mg 
b. Administration 
*See Appendix B for detailed pre-injection procedures. 


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c. Storage 
Upon receipt, drugs will be refrigerated at 2C - 8C (36F - 46F).  DO NOT 
FREEZE.  Do not use beyond the expiration date.  Ranibizumab and 
Aflibercept vials will remain refrigerated.  Protect vials from direct light. Store in 
original carton until time of use.  
RANIBIZUMAB and AFLIBERCEPT VIALS ARE FOR SINGLE USE ONLY.  
Vials used for one subject may not be used for any other subject.   
 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES 
Subjects may continue to receive all medications and standard treatments 
administered for their conditions at the discretion of their treating physician.   
4.5 
STUDY ASSESSMENTS 
4.5.1 Assessments during the Treatment Period 
Patient will be evaluated in the clinic within 1-2 days and 5-7 days post 
injections. Each clinic visit will include slit lamp examination, indirect 
ophthalmoscopy, measurements of BCVA, intraocular pressure, ocular 
inflammation evaluation and pain evaluation using a standard pain scale. 
4.5.2 Early Termination Assessments 
Subjects who withdraw from the study prior to completion should return for an 
early termination evaluation 1 day ( 1 days) following the injection for 
monitoring of all adverse events (serious and nonserious).  The schedule of 
assessments for early termination is the same as that for the final visit. 
 
4.6  
SUBJECT DISCONTINUATION 
A subject will be withdrawn from the study if he/she is enable to follow-up in 
the clinic per study protocol. If a subject decides to withdraw from the study, 
he/she will be scheduled for a follow up visit in 1 month as done routinely with 
neovascular macular degeneration patients.  
Subjects have a right to withdraw from the study at any time.   
The subject may be withdrawn from the study for any reasons: if it is in the 
best interest of the subject, intercurrent illness, adverse events, or worsening 


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condition.  The Sierra Eye Associates or Arshad Khanani M.D. 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: 
• Sensory 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 
• Need for therapy other than ranibizumab or aflibercept 
• SAE 
• Any other safety concerns 
In the event of an adverse event in the study eye that is considered by the 
investigator to be severe in intensity, serious consideration should be given to 
discontinuing the subject from the study.   
 
4.7 
STUDY DISCONTINUATION 
This study may be terminated by Sierra Eye Associates or Genentech at any 
time.  Reasons for terminating the study may include the following: 
• The incidence or severity of adverse events in this or other studies 
indicates a potential health hazard to subjects 
• Subject enrollment is unsatisfactory 
• Data recording is inaccurate or incomplete   
 
4.8 
STATISTICAL METHODS 
4.8.1 Analysis of the Conduct of the Study 
 
100 subjects will be enrolled in this study 
4.8.2 Safety Analyses 
Any adverse events, ocular examinations and measurements from all 100 subjects 


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will be reported. We will be evaluating patients 1-2 days (Visit 1) and again at 5-7 
days (Visit 2) post injection and reporting intraocular inflammation (defined as anterior 
chamber and/or vitreous cells) and pain (as measured on a standardized pain scale) 
and comparing them to baseline measurements. 
 
4.8.3 Efficacy Analyses 
Comparative analysis will be performed to evaluate for post injection pain and  
inflammation post aflibercept vs. ranibizumab injections. 
a.   Primary Endpoint 
Intraocular inflammation (defined as anterior chamber cells and flare or  
vitreous inflammation) will be evaluated at baseline, visit #1 and visit #2.  
Percentages of inflammation (present vs. absent) will be evaluated for  
each time point by treatment arm using a Chi-square test. Change in  
inflammation from baseline to visit #1 and baseline to visit #2 will be  
categorized as worse, same or better. Differences in change in  
inflammation between treatment arms will be evaluated using a Chi- 
square test. 
a.    Secondary Endpoints 
·    
Pain (as measured on a standardized pain scale) will be evaluated at baseline, 
visit #1 and visit #2. Pain at each time point will be compared between treatment 
arms using a Student’s t-test. Mean change in pain levels from baseline to visit #1 
and baseline to visit #2 will be calculated for each treatment arm. Student’s t-tests will 
be used to compare the mean change in pain between treatment arms.4.8.4
 
Missing Data 
Analyses of efficacy and safety will be based on available cases, without 
imputation for missing values.    
4.8.5 Interim Analyses 


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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.   
4.9 
DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of 
standard practices and procedures.     
 


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5. 
ASSESSMENT OF SAFETY 
 
Specification of Safety Variables 
  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) that are considered related to Ranibizumab and 
Aflibercept, all events of death, and any study specific issue of concern. 
 
5.1 
ADVERSE EVENTS 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other 
protocol-imposed intervention, regardless of attribution. 
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
Diabetic Macular Edema that were not present prior to the AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period. 
 
 
5.2 
SERIOUS ADVERSE EVENTS 
An AE should be classified as an SAE if the following criteria are met: 
• It results in death (i.e., the AE actually causes or leads to death). 
• It is life threatening (i.e., the AE, in the view of the investigator, places the 
subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. 
• It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the IMP. 


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• It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed above). 
 
 
5.3 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY 
VARIABLES 
 
The investigator is responsible for ensuring that all AEs and SAEs that are observed 
or reported during the study, are collected and reported to the FDA, appropriate 
IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports).  
 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after 
informed consent is obtained and initiation of study treatment and ends 7 days 
following the administration of study treatment or study discontinuation/termination, 
whichever is earlier. After this period, investigators should only report SAEs that are 
attributed to prior study treatment. 
 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by 
its duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 
suspected relationship to the study drugs (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
Yes 
 
There is a plausible temporal relationship between the onset of the AE and 
administration of the Ranibizumab or Aflibercept, and the AE cannot be readily 
explained by the subject’s clinical state, intercurrent illness, or concomitant therapies; 
and/or the AE follows a known pattern of response to the Ranibizumab or Aflibercept; 
and/or the AE abates or resolves upon discontinuation of the Ranibizumab or 
Aflibercept or dose reduction and, if applicable, reappears upon re-challenge. 
 
No 
 
Evidence exists that the AE has an etiology other than the Ranibizumab or Aflibercept 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
Ranibizumab or Aflibercept administration (e.g., cancer diagnosed 2 days after first 
dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in 
the Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified. This includes adverse events for which 
the specificity or severity is not consistent with the description in the P.I. or I.B. For 
example, under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. 
only referred to elevated hepatic enzymes or hepatitis. 
 
 
 
 
5.4 
EVALUATIONS 
Reviews of body systems will be performed.  A masked physician will be 
evaluating anterior chamber and vitreous inflammation using a slit lamp.. 
Anterior and vitreous inflammation will be graded using the standardized 
grading systems in Appendix D. 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
Ophthalmologic evaluations will include slitlamp examination, dilated 
examination, dilated binocular indirect high-magnification ophthalmoscopy, 
OCT, measurements of BCVA and intraocular pressure. (See Section 4.5 for a 
detailed description of the study assessments.) 
5.5 
VITAL SIGNS 
Will not be measured  
 
5.6 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING 
ADVERSE EVENTS 
5.6.1 Eliciting Adverse Events  
 
A consistent methodology for eliciting AEs at all subject evaluation timepoints should 
be adopted. Examples of non-directive questions include:  
• “How have you felt since your last clinical visit?” 
• “Have you had any new or changed health problems since you were last 
here?”  
 
5.6.2 Specific Instructions for Recording Adverse Events 
 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
a. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, it is ok to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
b. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 
5.1.2), regardless of attribution, will be reported to the appropriate parties. When 
recording a death, the event or condition that caused or contributed to the fatal 
outcome should be reported as the single medical concept. If the cause of death is 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
unknown and cannot be ascertained at the time of reporting, report “Unexplained 
Death”. 
c. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE 
only if the frequency, severity, or character of the condition worsens during the study. 
When reporting such events, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”). 
d. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a medical 
or surgical procedure as a result of an AE, the event responsible for the procedure, 
not the procedure itself, should be reported as the SAE. For example, if a subject is 
hospitalized to undergo coronary bypass surgery, record the heart condition that 
necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
e. 
Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 
30 days after the last dose of study drug, a report should be completed and 
expeditiously submitted to the Genentech, Inc. Follow-up to obtain the outcome of the 
pregnancy should also occur. Abortion, whether accidental, therapeutic, or 
spontaneous, should always be classified as serious, and expeditiously reported as 
an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the {study drug} should be reported as an SAE. 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
f. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior Ranibizumab or 
Aflibercept exposure. If the investigator should become aware of the development of 
cancer or a congenital anomaly in a subsequently conceived offspring of a female 
subject who participated in the study, this should be reported as an SAE.  
 
g. 
Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the 
Sponsor will agree to the reconciliation periodicity and format, but agree at minimum 
to exchange monthly line listings of cases received by the other party. If discrepancies 
are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a 
case-by-case basis until satisfactory resolution. 
 
h. AEs of Special Interest (AESIs) 
AEs of Special Interest are defined as a potential safety problem, identified as a result 
of safety monitoring of the Product. 
 The Lucentis Events of Special Interest are: 
• Retinal pigment epithelial tear 
• Increased intraocular pressure to > 30mm Hg not responsive to maximal 
topical IOP-lowering drugs measured on 2 separate days  
• Traumatic cataract 
• Endophthalmitis 
• Intraocular inflammation of greater than 2+ cells (including vitritis and uveitis) 
• Retinal detachment 
• ATEs, including stroke 
 
i. 
SAE Reporting 
Investigators must report all SAEs to Genentech within the timelines described below. 
The completed Medwatch/case report should be faxed immediately upon completion 
to Genentech Drug Safety at: 
 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
(650) 225-4682 
OR 
(650) 225-5288 
 
• Relevant follow-up information should be submitted to Genentech Drug Safety 
as soon as it becomes available. 
• Serious AE reports that are related to the Ranibizumab or Aflibercept and AEs 
of Special Interest (regardless of causality) will be transmitted to Genentech 
within fifteen (15) calendar days of the Awareness Date. 
• Serious AE reports that are unrelated to the Ranibizumab or Aflibercept will be 
transmitted to Genentech within thirty (30) calendar days of the Awareness 
Date. 
Additional Reporting Requirements to Genentech include the following: 
• Any reports of pregnancy following the start of administration with the 
Ranibizumab or Aflibercept will be transmitted to Genentech within thirty (30) 
calendar days of the Awareness Date.  
• 
All Non-serious Adverse Events originating from the Study will be forwarded in 
a quarterly report to Genentech. 
 
Note: Investigators should also report events to their IRB as required. 
 
5.6.3 MedWatch 3500A Reporting Guidelines 
 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500A form: 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
5.6.4 Follow-up Information 
Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with 
the original MedWatch 3500A form  
• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, 
if assigned, brief adverse event description, and notation that additional or 
follow-up information is being submitted (The patient identifiers are important 
so that the new information is added to the correct initial report) 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
Occasionally Genentech may contact the reporter for additional information, 
clarification, or current status of the patient for whom and adverse event was reported. 
For questions regarding SAE reporting, you may contact the Genentech Drug Safety 
representative noted above or the MSL assigned to the study. Relevant follow-up 
information should be submitted to Genentech Drug Safety as soon as it becomes 
available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
 
 
 


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5.6.6 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
AE / SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-5288 
 
Genentech Study Number 
ML29634 
Principal Investigator 
Arshad Khanani M.D. 
Site Name 
Sierra Eye Associates 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
6.0 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file with 
Sierra Eye Associates or its appointed representative:  
• FDA correspondence letter assigning an IND number or an IND waiver 
letter 
• Original U.S. FDA Form 1571 (if applicable) 
• Original U.S. FDA Form 1572 (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal 
Investigator (if applicable) 
• The names of any sub-investigators must appear on this form.  
Investigators must also complete all regulatory documentation as required 
by local and national regulations. 
• Current curricula vitae of the Principal Investigator  
• Medical License 
• Written documentation of IRB approval of the protocol (identified by Sierr 
Eye Associates], protocol number or title and date of approval)  
• IRB Approved protocol 
• Fully executed contract 
• Documentation of registration into clinical research website (e.g., 
www.clinicaltrials.gov) (as applicable) 
• Investigator Brochure Signature Receipt 
6.2 
STUDY COMPLETION 
The following data and materials are required by Sierra Eye Associates before 
a study can be considered complete or terminated: 
• Laboratory findings, clinical data, and all special test results from 
screening through the end of the study follow-up period (if applicable) 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
• Case Report Forms properly completed by appropriate study personnel 
and signed and dated by the investigator (if applicable) 
• Copies of protocol amendments and IRB approval/notification (if 
applicable) 
• A summary of the study prepared by the Principal Investigator (will 
accept IRB summary close letter) (if applicable) 
• All regulatory documents (e.g., curricula vitae for each Principal 
Investigator, U.S. FDA Form 1571 and 1572) 
 
6.3      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 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 which may 
reasonably be expected from the research. A description that there may 
be no benefit from this research. 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
• 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 FDA and the Sierra Eye Associates and the 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 research patient’s 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 
 
6.4 
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 
U.S. FDA, 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 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
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 provided by Sierra Eye Associates (e.g., IND safety report, 
Investigator Brochure, safety amendments and updates, etc.). 
 
6.5 
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. 
 
6.6 
STUDY DRUG ACCOUNTABILITY 
The Investigator is responsible for the control and distribution of study drug. 
All partially used or empty containers should be disposed of at the study site 
according to institutional standard operating procedure.  
 
6.7 
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 U.S. FDA, national and local health authorities, the drug 
manufacturer and the IRB/EC for each study site, if appropriate. 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
 
6.8 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents 
pertaining to the conduct of this study and the distribution of investigational 
drug, including CRFs, consent forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 2 years 
after the investigation is discontinued and the U.S. FDA and the applicable 
national and local health authorities are notified. 
 
 
6.9 
STUDY CLOSE-OUT 
The Clinical Study Report (final study report) will be emailed to lucentisgsr_coa-
d@gene.com or faxed to 866-728-4622 . Additionally, any literature articles that are a result 
of the study should be sent to Genentech. Copies of such reports should be mailed to the 
assigned contact for the study. 
 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
REFERENCES 
 
1. Khanani et al. Evaluation of Intraocular Inflammation and Pain Post Intravitreal 
Injection of Ranibizumab or Aflibercept: The PLANET Study. Presented at ASRS 
2014. San Diego, CA. 
2. Hahn P et al. Aflibercept-related sterile inflammation. Ophthalmology. 2013 May;120(5):1100-
101 
3. Goldberg RA et al. Noninfectious Inflammation After Intravitreal Injection of 
Aflibercept: Clinical Characteristics and Visual Outcomes. Am J Ophthalmol. 2014 Jun 
28 
4. Kiss et al. The Pattern of Anti-VEGF Use in Neovascular Age- Related Macular 
Degeneration and Diabetic Macular Edema: A US Claims Analysis. Presented at 
ASRS 2014, San Diego, CA. 
5. Fine et al. Frequency and Management of Intraocular Inflammation after Aflibercept 
injection. Presented at ASRS 2014, San Diego, CA. 
6. Jabs, DA et al. Standardization of uveitis nomenclature for reporting clinical data. Results of 
the First International Workshop. Am J Ophthalmol. 2005;140:509-16. 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
APPENDIX A 
Study Flowchart  
 
 
Procedure 
Day 0 
Visit 1 (24-48 
hours post Day 0) 
Visit 2 (5-7 Days 
post Day 0) 
Informed Consent 
X 
 
 
Randomization 
X 
 
 
Demographic Data 
X 
 
 
Medical and Ophthalmic history (including 
specifics on ophthalmic history, any 
previous injections with agent and 
month/year, and any prior surgeries 
within past two years.) 
X 
 
 
Slit lamp exam and OCT 
X 
X 
X 
Indirect ophthalmoscopy exam 
X 
X 
X 
Treatment Assignment 
X 
 
 
BCVA and Intraocular pressure 
X 
X 
X 
Ranibizumab  or Aflibercept treatmentb 
X 
 
 
Ocular Inflammation Evaluation 
X 
X 
X 
Pain Evaluation 
X 
X 
X 
AE / SAE monitoring 
 
X 
X 
 
 
 
 
 
 
 
 
 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
APPENDIX B 
Pre-Injection Procedures for All Subjects 
 
The following procedures will be implemented to minimize the risk of potential 
adverse events associated with serial intravitreal injections (e.g., endophthalmitis).  
Aseptic technique will be observed by clinic staff involved in the injection tray 
assembly, anesthetic preparation, and study drug preparation and administration.  In 
addition to the procedures outlined below, added 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 investigator.   
• The technician assembles the supplies and prepares a sterile field.  Supplies 
include 10% povidone iodine swabs, sterile surgical gloves, 44 sterile pads, pack 
of sterile cotton-tipped applicators, eyelid speculum, sterile ophthalmic drape, 
0.5% proparacaine hydrochloride, 5% povidone iodine ophthalmic solution, 
1% lidocaine for injection, and injection supplies. 
• Instill 2 drops of 0.5% proparacaine hydrochloride into the study eye 
• Disinfect the periocular skin and eyelid of the study eye in preparation for 
injection.  Scrub the eyelid, lashes, and periorbital skin with 10% povidone iodine 
swabs, starting with the eyelid and lashes and continuing with the surrounding 
periocular skin.  Make certain that the eyelid margins and lashes are swabbed, 
and proceed in a systematic fashion, from medial to temporal aspects. 
• The investigator will glove, and place the speculum underneath the eyelid of the 
study eye. 
• Instill 2 drops of 5% povidone iodine ophthalmic solution in the study eye, making 
sure the drops cover the planned injection site on the conjunctiva. 
• Wait 90 seconds. 
• Saturate a sterile cotton-tipped applicator with 0.5% proparacaine hydrochloride 
drops and hold the swab against the planned intravitreal injection site for 
10 seconds in preparation for the subconjunctival injection of 1% lidocaine 
hydrochloride ophthalmic solution for injection (without epinephrine). 
• Use a sterile 44 pad in a single wipe to absorb excess liquid and to dry the 
periocular skin. 
• Instruct subject to direct gaze away from syringe prior to ranibizumab or 
aflibercept injection. 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
APPENDIX C 
Analysis of Similar Events Template for IND Safety Reports 
 
IND Safety Report 
Case Summary 
This section will be initiated by a research coordinator and may be modified by principal  investigators 
if necessary.  The case summary should describe the reported AE in detail, including a description of 
what happened and a summary of all relevant clinical information (e.g. medical status prior to the 
event, signs, symptoms, diagnoses, clinical course, treatment, outcome, etc.)  The IND safety report 
should not identify the subject ID #, reporting investigator, or the site as this information may 
compromise the study blind. 
 
PREVIOUS REPORTS  
The information for this section comes from Principal Investigator and the search of similar events.  
This section should be written by the responsible principal investigator. 
 
*  Select one of the following two  statements after reviewing the search of similar events results. 
Under IND _______(insert IND#), the following IND safety reports of similar AEs have been previously 
submitted: 
MCN 
Reported Event 
Submission Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Or 
 
Under IND _______ (insert IND#), no IND safety reports of similar AEs have been submitted 
previously. 
In addition to previously submitted IND safety reports of similar events, this section can also 
summarize pervious serious reports of the same/similar event that were considered unrelated to the 
investigational product at the time of the reporting.  These events would remain blinded, unless a 
decision to unblind is made by an Independent Monitoring Committee for reasons of subject 
protection.  The decision on what similar events to summarize in this section should be made after 
reviewing  the similar events report generated by Clinical Data Management.  If a safety signal is 
particularly  worrisome (e.g., a study stopping type of event), a more extensive evaluation may be 
required. 
 
Assessment of Relationship 
After evaluation the new case report and reviewing any relevant previous reports of similar events, the 
PI selects one of the following boilerplate conclusion statements, if applicable.  The PI may also craft 
an alternative conclusion. 
Based on review of available data, Sierra Eye Associates believes there is a reasonable possibility of a 
cause-and-effect relationship between administration of _____________(insert study drug name) and 
the occurrence of _____________( insert AE). 
Additional information on risk factors and/or treatment of the AE may be provided if warranted. 


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Or 
Based on review of available data, the Sierra Eye Associates does not believe that there is a 
reasonable possibility of a cause-and-effect relationship between administration of _______(insert 
study drug name) and the occurrence of ___________(insert AE). 
Explain if warranted.  Do not speculate. 
 
 
 
 
 
Or 
Based on review of available data, the Sierra Eye Associates cannot establish or exclude the 
possibility of a cause-and-effect relationship between administration of __________(insert study drug 
name) and the occurrence of __________(insert AE). 
Explain if warranted.  Do not speculate. 
After review of the clinical details and investigator’s comments pertaining to this AE, and based on 
experience to date, the Sierra Eye Associates does not believe that changes to the conduct of this 
clinical trial are warranted.  This statement can be modified if changes to the conduct of the clinical trial 
are made. 
 
 
 
 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
APPENDIX D 
 
Anterior Chamber Cell 
Grade 0                <1 cells 
Grade 0.5+          1-5 cells 
1+                           6-15 cells 
2+                           16-25 cells 
3+                           26-50 cells 
4+                           >50 cells 
 
Anterior Chamber Flare 
0                              No flare 
1+                           Faint 
2+                           Moderate (iris and lens details clear) 
3+                           Marked (iris and lens details hazy) 
4+                           Intense (fibrous or plastic aqueous) 
 
Vitreous Cell Grade 
0                              No haze 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
0.5                           Trace - Slight blurring of Optic Nerve (ON) border 
1+                           Slightly blurry ON plus margins 
2+                           Moderately blurred ON plus vessels 
3+                           ON border blurry, just visible 
4+                           ON obscured 
 
 
 


Protocol:  ML29634 Final 
     
 
 
 
                                                                                                              
 
 
APPENDIX E 
 
NUMERICAL RATING SCALE FOR PAIN 
 
An 11 point numerical rating scale from 0-10 will be administered to each 
patient verbally.  Patients are asked to verbally rate their pain "on a scale from 
0 to 10, with 0 equal to no pain and 10 equal to worst possible pain."  Each 
patient will be read the following script, with no deviations: 
 
"I am going to ask you to rate the level of pain you felt from your injection on a 
scale from 0 to 10.  A rating of zero means you experienced no pain at all. 
 Ratings from 1-3 designate mild levels of pain.  Ratings from 4-6 designate 
moderate levels of pain.  Ratings from 7-9 designate severe levels of pain.  A 
rating of 10 designates the worst possible pain.  Please tell me, on this scale 
from 0-10, what level of pain you felt from your injection?"