Clinical trial NCT01982435
Conditions: Diabetic Macular Edema
Keywords: Diabetes Macular Edema
Sponsor: Justis Ehlers
Start date: 2014-06-24; Completion date: 2016-05-26
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to assess the ocular and systemic adverse events of ranibizumab (Lucentis)for DME (diabetic macular edema) following previous treatment with intravitreal bevacizumab (Avastin).

Detailed description:
This is an open-label, Phase I/II study of intravitreally administered 0.3mg ranibizumab (Lucentis) in subjects with DME (diabetic macular edema) previously treated with intravitreal bevacizumab (Avastin) with a randomized comparative dosing strategy, monthly vs "treat-and-extend." Thirty patients total will be enrolled in the study, 15 in each group. This study will have a 1-year treatment period. The recruitment period will occur over 1 year with total potential study duration of 2 years.

Arms: arm 1: Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. arm 2: Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results.
Interventions: intervention 1: Ranibizumab intervention 2: Ranibizumab
Intervention descriptions: intervention 1: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema. intervention 2: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.

Protocol documents:
SAP_002.pdf: 
REACT Study 
 
Safety and Efficacy of Intravitreal Ranibizumab for Diabetic Macular 
Edema Previously Treated with Intravitreal Bevacizumab: A Randomized 
Dual-Arm Comparative Dosing Trial (Phase:1/2):  
 
IND 120427  
NCT01982435  
Statistical Analysis Plan  
11‐07‐2013  
Measures for this study will be summarized using means, range and standard error of the means (SEM). 
Two‐sided paired t‐tests and two‐sided unpaired t‐tests will respectively be conducted to analyze 
efficacy endpoints between study initiation to end, and between monthly and Treat and extend 
injection regimens. Patients who exit the study early can be accounted for by using a last observation 
carried forward approach. Chi‐squared analysis will be used to assess significant differences in 
ophthalmic adverse event frequency. All analyses will be performed using GraphPad Prism 5 (GraphPad 
Software, La Jolla, California, USA) with a significance level of 0.05 being assumed for all tests 

Prot_000.pdf: 
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PROTOCOL 
STUDY TITLE: 
Safety and Efficacy of Intravitreal Ranibizumab 
for Diabetic Macular Edema Previously Treated 
with Intravitreal Bevacizumab:  A Randomized 
Dual-Arm Comparative Dosing Trial 
(Phase:1/2):  REACT Study 
STUDY DRUG 
Recombinant humanized anti-VEGF 
monoclonal antibody fragment (rhuFab V2 
[ranibizumab]) 
 
SPONSOR 
Genentech 
 
IND: 
120427 
 
 
INVESTIGATOR 
Justis P. Ehlers, MD  
 
SUB-
INVESTIGATORS 
Rishi P. Singh, MD 
Peter Kaiser, MD 
Dan F. Martin, MD 
Sunil K. Srivastava 
Alex Yuan, MD PhD 
Andrew P. Schachat, MD 
Jonathan Sears, MD 
DATE FINAL: 
27/2/2017 
AMENDMENT: 
 
      Number 4, Date: 27/2/2017 
NCT #  
 
 
      01982435 


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TABLE OF CONTENTS 
 
                         Page:         
1. 
BACKGROUND ........................................................................................... 1-6  
1.1 
Pathophysiology ................................................................................ 1 
1.2 
Treatment .......................................................................................... 1-2 
1.3 
Ranibizumab ..................................................................................... 2-3 
1.4 
Nonclinical Experience with Ranibizumab ......................................... 3-6 
1.4.1 
Nonclinical Pharmacokinetics .............................................. 3 
1.4.2 
Nonclinical Toxicology ......................................................... 4 
1.4.3 
Stability Studies ................................................................... 4 
1.5 
Clinical Experience with Ranibizumab ............................................... 4-6 
2. 
OBJECTIVES ............................................................................................... 6-7 
 
2.1 
Primary Objective    ………………………………………………………7 
 
2.2 
Secondary Objective ……………………………………………………. 7 
3. 
STUDY DESIGN .......................................................................................... 8-10 
3.1 
Description of the Study .................................................................... 8 
3.2 
Rationale for Study Design ................................................................ 8-9 
3.3 
Outcome Measures ........................................................................... 9 
3.3.1 
Primary Outcome Measures ................................................ 9 
3.3.2 
Secondary Outcome Measures ........................................... 9 
3.4 
Safety Plan ........................................................................................ 9-10 
3.5 
Compliance with Laws and Regulations ............................................ 10 
4. 
MATERIALS AND METHODS ..................................................................... 10-21 
4.1 
Subjects ............................................................................................ 10-12
 ..........................................................................................................  
4.1.1 
Subject Selection ................................................................. 10-11 


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TABLE OF CONTENTS (cont’d) 
 
                   Page 
4. 
MATERIALS AND METHODS (cont’d) 
4.1.2 
Inclusion Criteria .................................................................. 11  
4.1.3 
Exclusion Criteria ................................................................. 11-12 
4.2 
Method of Treatment Assignment ………………………………………12    
4.3 
Study Treatment ................................................................................ 13-15 
4.3.1 
Formulation .......................................................................... 13  
4.3.2 
Dosage, Administration, and Storage .................................. 13-15 
4.4 
Concomitant and Excluded Therapies ............................................... 15  
4.5 
Study Assessments ........................................................................... 15-19 
4.5.1 
Assessments during the Treatment Period .......................... 15-19 
4.5.2 
Early Termination Assessments........................................... 19  
4.6  
Subject Discontinuation ..................................................................... 19-20 
4.7  
Study Discontinuation ........................................................................ 20 
4.8  
Statistical Methods ……………………………………………………….20-21    
 
4.8.1      Analysis of the Conduct of the Study ................................... 20  
4.8.2 
Safety Analyses ................................................................... 20 
4.8.3 
Efficacy Analyses ................................................................. 21  
4.8.4 
Missing Data ........................................................................ 21  
4.8.5 
Interim Analyses ………………………………………………..21 
 
4.9 
Data Quality Assurance ………………………………………………….21 
5. 
ASSESSMENT OF SAFETY ........................................................................ 22-32 
5.1 
Adverse Events ................................................................................. 22  
5.2 
Serious Adverse Events .................................................................... 23 
5.3 
Methods and Timing for Assessing and Recording Safety Variables 23-24 
5.4 
Evaluations ........................................................................................ 24-25 
5.5 
Vital Signs ......................................................................................... 25 
5.6 
Procedures for Eliciting, Recording, and Reporting Adverse Events . 25-32 
 
 
 
 
 
 
 


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TABLE OF CONTENTS (cont’d) 
 
                   Page 
 
5.6.1 Eliciting Adverse Events .................................................................... 25 
 
5.6.2 
Specific Instructions for Recording Adverse Events............. 25-28 
 
5.6.3 
Med Watch 3500A Reporting Guidelines ……………………28 
 
5.6.4 
Follow-up Information .......................................................... 28-29 
 
5.6.5 
Additional Reporting Requirements for IND Holders………. 29-31 
 
 
5.6.6  
Safety Reporting Fax Cover Sheet ...................................... 32 
6      INVESTIGATOR REQUIREMENTS ............................................................. 33-37 
6.1 
Study Initiation ................................................................................... 33  
6.2 
Study Completion .............................................................................. 33-34 
6.3 
Informed Consent Form .................................................................... 34-35 
6.4 
Institutional Review Board or Ethics Committee Approval ................. 35-36 
6.5 
Case Report Forms ........................................................................... 36  
6.6 
Study Drug Accountability………………………………………………..36  
6.7 
Disclosure of Data ............................................................................. 36   
6.8 
Retention of Records ......................................................................... 37  
 
6.9  
Study Close-Out ................................................................................ 37 
REFERENCES .................................................................................................... 38-39 
 
 
APPENDICES 
Appendix A: 
Study Flowchart……………………………………………………..40-42     
Appendix B: 
Pre-Injection Procedures for All Subjects…………………………43 
Appendix C: 
 Analysis of Similar Events ………………………………………..44-45    
 


 
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1. 
BACKGROUND 
1.1 
PATHOPHYSIOLOGY 
Diabetic macular edema (DME) is the most common cause of vision loss from 
diabetic retinopathy.  It is characterized by macular swelling secondary to 
increased vascular permeability secondary to loss of pericytes in the macular 
vascular bed.  Clinically, microaneurysms and exudates are often seen in 
association with macular edema.  Foveal-involving cystic changes and 
macular edema can have significant impact on visual loss.  Extent of perfusion 
and ischemia also is important for visual prognosis.   
Multiple factors play a role in the evolution of diabetic macular edema.  
Vascular endothelial growth factor has been shown to be significantly elevated 
in diabetic retinopathy and may play an important role in the evolution and 
pathogenesis of DME.   Increasing VEGF levels are also seen in the setting of 
progressive ischemia, such as proliferative diabetic retinopathy when 
extensive peripheral nonperfusion may be present.1  Reducing the active 
levels of VEGF may have significant positive consequences for outcomes 
related to DME management.  
 
1.2 
TREATMENT OF DIABETIC MACULAR EDEMA 
Following the Early Treatment of Diabetic Retinopathy Study (ETDRS), 
focal/grid laser photocoagulation became the standard treatment for DME.  
This therapy may continue to have an important place in the treatment of 
macular edema.  Utilizing laser photocoagulation, the ETDRS achieved 
stabilized vision for a significant number of patients with diabetic macular 
edema.2 
However, advances in pharmacotherapy have resulted in exciting new 
treatment modalities for DME.  The Diabetic Retinopathy Clinical Research 
Network (DRCR.net) conducted a study comparing intravitreal triamcinolone to 
laser photocoagulation.  In this study laser photocoagulation performed better 
over the long-term with reduced side effects.3  However, other studies have 
suggested that particularly in pseudophakic patients, steroids are an important 
treatment alternative.4  Long-lasting steroid delivery systems are also currently 
under investigation, including a dexamethasone implant and fluocinolone 
implant.  Results from these studies are promising but at this time these 


 
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devices are still under investigation and are not FDA-approved in the United 
States.5, 6 
Since the initial publication of the DRCR.net  study that suggested superiority 
of ranibizumab to laser photocoagulation, VEGF inhibitors have become a 
first-line therapy for DME.4  Bevacizumab which is not approved for ophthalmic 
indications is among the most frequently used anti-VEGF agents.    The BOLT 
study was a 2-year randomized controlled trial comparing bevacizumab to 
laser photocoagulation.  Bevacizumab was given with a loading does every 6 
weeks for three injections and then retreatment occurred every 6 weeks.  
Bevacizumab performed significantly better than the laser group with a median 
gain of 9 letters compared to 2.5 letters.  Nearly 50% of eyes gained 2 lines or 
more compared to 7% of the laser group.7, 8 Given the limited size of the 
bevacizumab studies, conclusions regarding safety remain difficult. 
Alfibercept is also being studied in the treatment of DME.  In comparison to 
laser photocoagulation, the various dosing regimens of aflibercept showed a 
9.7-12.0 letter gain compared to -1.3 letters for the laser group.    When 
examining eyes with 3 line gain or more, 23.8-45.5% of eyes treated with 
aflibercept compared to 11.4% for the laser group.9  Aflibercept remains 
investigational at this time for the treatment of DME. 
Ranibizumab is the first and currently only VEGF inhibitor approved for the 
treatment of DME.  The results of the RISE/RIDE trials showed that 33.6 to 
44.8% of eyes gained more than 3 lines at 2 years compared to 12.3-18.3% of 
sham eyes.  Laser photocoagulation was allowed as a rescue therapy.  Based 
on the results of the RISE/RIDE trials, the FDA approved ranibizumab 0.3 mg 
for the treatment of DME in August 2012.10 
 
1.3 
RANIBIZUMAB AND DIABETIC MACULAR EDEMA 
 
As noted above, the pivotal RISE/RIDE phase III trials resulted in the FDA 
approval of ranibizumab for the treatment of DME.  Numerous trials have 
suggested the efficacy and safety of ranibizumab in the treatment of DME, 
including the DRCR.net, READ, and RISE/RIDE.4, 10, 11  The results of these 
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treatment modality for DME.  Ranibizumab therapy results in functional 
stabilization in the vast majority of eyes and in significant improvement in 
nearly half of eyes.  Additionally, RISE/RIDE revealed that eyes treated with 
ranibizumab had lower rates of retinopathy progression and higher rates of 
retinopathy improvement.  In addition to the functional improvements, 
ranibizumab resulted in significant anatomic improvements with a mean 
reduction of ~ 250 microns in central foveal thickness compared to only 133 
micron decrease in the laser group.10   
 
Prior to the approval of ranibizumab, bevacizumab was the only readily 
available VEGF inhibitor being utilized (off-label) for the treatment of DME.  
Although the functional results to bevacizumab therapy, appear promising, the 
systemic safety of bevacizumab for DME and the relative efficacy of 
bevacizumab compared to ranibizumab remain unknown.  With ranibizumab’s 
approval, it is unclear whether switching from bevacizumab to ranibizumab has 
a clinical impact on the disease course.  Given the number of eyes treated with 
bevacizumab, answering this question is important.  These questions are the 
focus of this investigation.   
  
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. 
 


 
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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 
Ranibizumab has been or is being studied in more than 5000 subjects with 
neovascular AMD, retinal vascular occlusive disease, and diabetic 
retinopathy/macular edema in a number of Phase I, I/II, II, III, and IIIb clinical trials.  .  
Ranibizumab is contraindicated in patients with ocular or periocular infections and in 
those with known hypersensitivity to ranibizumab or any of the excipients in 
ranibizumab.  Intravitreal injections, including those with ranibizumab, have been 
associated with endophthalimits and retinal detachment.  Proper aseptic injection 
technique should always be used when administering ranibizumab.  Increases in IOP 
have been noted within 60 minutes of intravitreal  injection with ranibizumab.  
Therefore, IOP as well as perfusion of the optic nerve head should be monitored and 
managed appropriately.  Serious adverse events related to the injection procedure 
have occurred in <0.1% of intravitreal injections include endophthalmitis, 
rhegmatogenous retinal detachment, and iatrogenic traumatic cataract.  Other serous 
ocular adverse events observed among ranibizumab-treated subjects and occurring in 
<2% of subjects included intraocular inflammation and increased IOP.  The most 
common adverse reactions (reported > 6% higher in ranibizumab-treated subjects 


 
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than control subjects) were conjunctival hemorrhage, eye pain, vitreous floaters, 
increased IOP, and intraocular inflammation. 
 
Although there was a low rate (<4%) of arterial thromboembolic events  (ATEs) 
observed in the ranibizumab clinical trials there is a potential risk of ATEs following 
intravitreal use of inhibitors of VEGF.  The rate of ATEs in three studies (FVF2598g, 
FVF2587g, and FVF3192g) in the first year was1.9% of subjects in the combined group 
of subjects treated with 0.3 mg or 0.5 mg ranibizumab compared with 1.1% of subjects 
in the control arms of the studies.  In the second year of Study FVF2598g and 
FVF2587g, the rate of ATEs was 2.6% of subjects in the combined group of those 
treated with 0.3 mg or 0.5 mg ranibizumab compared with 2.9% of subjects in the 
control arm.  The most common non-ocular adverse reactions observed in > 15% of 
ranibizumab-treated subjects that occurred more frequently than in control subjects 
included, nasopharyngitis, headache, and upper respiratory tract infection. 
  
The Sailor study (FVF3689g) evaluated the safety of intravitreal ranibizumab in 
a large population of subjects with CNV secondary to AMD.  Subjects in Cohort 
1 (N=2378) were randomized (1:1) to receive ranibizumab at a dose level of 0.3 
mg or 0.5 mg; subjects were masked to these dose levels.  Treatment was 
administered monthly for three initial doses (Day 0, Month 1, and Month 2), with 
scheduled follow-up visits on Months 3,6,9, and 12.  Retreatment after the first 
three injections was performed as needed, on the basis of predefined criteria 
with injections no more frequently than every 30 days. 
 
Cohort 2 (N=1992) consisted of subjects enrolled after the majority of Cohort 1 
subjects had been enrolled, with enrollment continuing until ranibizumab was 
approved or denied by the FDA for US marketing, and if approved, until 
commercially available or 30 September 2006, whichever was earlier.  Subjects 
in Cohort 2 received open-label ranibizumab at the 0.5 mg dose level, with an 
initial injection on Day 0 followed by retreatment at the physician’s discretion, no 
more frequently than every 30 days.  Subjects were monitored for safety for a 
total of 12 months; safety information, including both serious and nonserious 
adverse events, was collected at every clinic visit, with two formal safety visits 
scheduled at Months 6 and 12. 
 


 
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The study consisted of a 30-day screening period and a 1-year treatment 
period.  Treatment duration was approximately 197 days for both dose groups 
in Cohort 1 and 144 days for subjects in Cohort 2.  The mean follow-up time 
differed between Cohort 1 and Cohort 2, 337 days versus 254 days, 
respectively. 
 
Ranibizumab was well tolerated, and the incidence of ocular SAEs and AEs 
was low and unrelated to dose.  The rates of individual key ocular SAEs in 
Cohort 1 were < 1% and were similar across dose groups.  Endophthalmitis or 
presumed endophthalmitis developed in 0.2% subjects in the 0.3-mg group and 
0.4% subjects in the 0.5-mg group.  The incidence of ocular inflammation, 
including iritis, uveitis, vitritis, and iridocylitis was 1.9% in the 0.3-mg group and 
1.5% in the 0.5-mg group.  Overall cataract rates were 5.4% (0.3 mg) and 6.0% 
(0.5 mg) and were similar when broken down by nuclear, subcapsular, and 
cortical subtypes.  The rates of individual key ocular SAEs in Cohort 2 were 
<1%. 
 
The rates of key non-ocular SAEs and AEs, including Antiplatelet Trialists’ 
Collaboration (APTC) ATEs, MI, and vascular death were similar for cohorts 1 
and 2 and 0.3- and 0.5-mg dose groups.  The incidence of MI and non-ocular 
hemorrhage was similar across Cohort 1 dose groups.  APTC ATEs, including 
vascular and unknown deaths, nonfatal MI, and nonfatal cardiovascular 
accidents, were similar across dose groups.  During the 12-month study period, 
0.7% of subjects in the 0.3-mg group and 1.2% of subjects in the 0.5-mg group 
suffered a stroke.  The number of vascular deaths and deaths due to unknown 
cause did not differ across dose groups.  Rates of key non-ocular SAEs in 
Cohort 2 were generally lower than those in Cohort 1. 
Refer to the Ranibizumab Investigator Brochure or Lucentis® Package Insert for 
additional details regarding clinical safety experience with ranibizumab. 
 
 
2. 
OBJECTIVES 
The utility and efficacy of ranibizumab in eyes with DME that are naïve to 
VEGF inhibitors has been shown in the RISE/RIDE trials and others. 
4,10,11However, many eyes have been previously treated (recent and frequent) 


 
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with other VEGF inhibitors (in particular, bevacizumab).  Our primary objective 
is to understand the functional and anatomic effectiveness of ranibizumab 
following previous anti-VEGF.  Additionally, the optimal dosing regimen 
remains to be determined.  Monthly dosing was evaluated in the RISE/RIDE 
trials, but monthly dosing may not be necessary or practical in all patients.  
This study will also compare a “treat-and-extend” dosing regimen to a monthly 
dosing regimen. 
2.1 Primary Objective 
The primary objective of the study is to assess the ocular and systemic 
adverse events of ranibizumab for DME following previous treatment with 
intravitreal bevacizumab (worsened acuity >30 letters, retinal detachment, 
endophthalmitis, cataract progression, vitreous hemorrhage, new PDR or 
neovascularization of the iris or angle, systemic thromboembolic events, 
deaths and systemic serious adverse events). 
 
2.2 Secondary Objectives  
 
The secondary objectives include: 
 mean change from baseline in best-corrected visual acuity at months 6 
and 12 
 mean absolute change from baseline central foveal thickness at 
months 6 and 12 as measured by SDOCT (defined as the average 
thickness within the central 1 mm subfield) 
 proportion of subjects that were anatomically “dry” by SDOCT at 
months 6 and 12 
 proportion of participants who gained greater than or equal to 15 letters 
of vision at months 6 and 12 
 proportion of participants who lost greater than or equal to 15 letters of 
vision at months 6 and 12 
 proportion of patients that are 20/40 or better at months 6 and 12 
 comparison of extent of angiography leakage from baseline to months 
3, 6, and 12, 
 comparison of peripheral nonperfusion from baseline to months 3, 6 
and 12 
 total number of injections 


 
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 Assessment of pre-trial anatomic improvement based on OCT on 
bevacizumab prior to switching to ranibizumab.  Analysis will also be 
stratified based on subsequent response to ranibizumab. 
 Assessment of pre-trial functional improvement based on snellen visual 
acuity prior to switching to ranibizumab.  Analysis will also be stratified 
based on subsequent response to ranibizumab. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an open-label, Phase I/II study of intravitreally administered 0.3mg 
ranibizumab in subjects with DME previously treated with intravitreal 
bevacizumab with a randomized comparative dosing strategy (monthly vs 
“treat-and-extend”).   Thirty patients total will be enrolled in the study, 15 in 
each group.  This study will have a 1-year treatment period.    The recruitment 
period will occur over 1 year with a total potential study duration of 2 years.  
Interim analysis performed at 6 months and final analysis at 1 year. 
Group 1 (monthly group) n=15 
 Consented, enrolled subjects will receive multiple open-label 
intravitreal injections of 0.3 mg ranibizumab administered every 
30 days (+/- 7 days from the last treatment) for 12 months in the 
monthly group.   
Group 2 (“treat-and-extend” group) n=15 
 In the “treat-and-extend” group, eyes will be treated with 3 
loading doses at 30-day intervals (+/- 7 days from the last 
treatment).  After the third loading dose, the follow-up interval is 
determined with an OCT-based protocol.   
Angiography assessment: 
Both qualititative and quantitative assessment of angiographic features will be 
performed on obtained angiograms.  This will include evaluation of leakage, 
microaneurysms and ischemia.   This is detailed in Appendix D.  Addendum for  
Prior anti-VEGF response assessment: 


 
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Utilizing available clinical and imaging data contained in the medical record, 
assessment of functional (visual acuity) and anatomic (OCT) responses will be 
assessed.   This information would be assessed in detail following review of 
this data for appropriate inclusion/exclusion parameters for the study.  This is 
detailed in Appendix E. 
 
3.2 
RATIONALE FOR STUDY DESIGN 
RISE/RIDE have shown that ranibizumab is an effective treatment for DME in anti-
VEGF naïve eyes.  However, many patients have been previously treated with 
bevacizumab or are initially started on bevacizumab.  The efficacy and safety of 
ranibizumab following previous bevacizumab therapy is unknown.  In addition to 
better understanding the role for ranibizumab following bevacizumab, this study also 
aims to evaluate a dosing regimen that reduces treatment/visit burden.  Diabetes is a 
chronic disease and often these patients are younger than the age-related macular 
degeneration population.  The burden of monthly visits and cumulative risk of monthly 
treatment over years should not be ignored and is likely not practical.  This study will 
evaluate one of the most popular anti-VEGF treatment regimens for neovascular age-
related macular degeneration:  “treat-and-extend.”   This novel approach minimizes 
visits and treatment while maximizing the anatomic results [minimizing the cycle of 
edema recurrence that triggers therapy in a pro re nata (PRN) regimen]. 
Addendum for Quantitative Assessment of Ultra-Widefield Angiographic 
Features in Diabetic Macular Edema 
Objective and quantitative assessment of angiographic imaging is currently 
lacking.  Subjective interpretation of angiographic patterns and features limit 
the analysis and potential of utilizing the modality as a true biomarker of 
diagnostic and therapeutic value.  The complex patterns noted within 
angiography, including staining, leakage, pooling, blockage, nonperfusion, and 
window defects are amenable to quantatitive assessment and integrative 
analysis for pattern recognition.  This complex pattern analysis could be 
utilized to create an activity fingerprint that may have value in therapeutic 
assessment and monitoring. 
Common angiographic features in DME in these conditions include vascular 
staining/leakage, microaneurysms, capillary nonperfusion, and 
neovascularization. Differential response to anti-VEGF therapy is quite 


 
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frequent among patients, vascular patterns and angiographic features may 
provide important insight into the optimal therapeutic or reason for lack of 
response.  The ability to objectively characterize the patterns and features of 
the angiographic features would be an important advance in characterizing 
retinal vascular conditions.  
 
3.3 
OUTCOME MEASURES 
3.3.1 Primary Outcome Measures 
 
The primary outcome measures for safety and tolerability are the following: 
 Incidence and severity of ocular adverse events, as identified by eye 
examination (including visual acuity testing) 
 Incidence and severity of other non-ocular adverse events, as identified by 
physical examination, subject reporting, and changes in vital signs 
 
3.3.2 Secondary Outcome Measures 
 Mean change in best-corrected visual acuity as assessed by the number of letters 
read correctly on the electronic ETDRS eye chart from baseline to months 6 and 
12. 
 Mean absolute change from baseline central foveal thickness at months 6 and 12 
as measured by SDOCT (defined as the average thickness within the central 1 
mm subfield) 
 Proportion of eyes that were anatomically “dry” by SDOCT at months 6 and 12. 
 Proportion of eyes gaining greater than or equal to 15 letters of vision at months 6 
and 12. 
 Proportion of eyes losing greater than or equal to 15 letters of vision at months 6 
and 12. 
 Proportion eyes with 20/40 or better best-corrected visual acuity at months 6 and 
12.  
 Comparison of extent of angiographic leakage from baseline to months 3, 6 and 
12. 
 Comparison of extent of peripheral nonperfusion from baseline to months 
3, 6, and 12. 
 Comparison of previous anatomic anti-VEGF response to month 3, month 
6, and month 12 anatomic response. 


 
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 Comparison of previous functional anti-VEGF response to month 3, month 
6 and month 12 functional response 
3.4 
SAFETY PLAN 
The safety assessments to be conducted for this study are listed in Section 4.5 
and Appendix A. 
Potential ocular adverse events associated with intravitreal injections include 
ocular irritation, subconjunctival hemorrhage, corneal abrasion, floaters, 
vitreous hemorrhage, retinal tear, retinal detachment, endophthalmitis, lens 
damage, and intraocular inflammation.  The risk of severe ocular side effects 
(e.g., endophthalmitis, retinal detachment) is approximately 1/1000.  Potential 
theoretical systemic adverse events include stroke and myocardial infarction.  
However, patients with diabetes are also at higher risk of stroke and 
myocardial infarction.  The incidence of these serious side effects were 2.4 to 
8.8% in the ranibizumab group compared to 4.9 to 5.5% in the sham group in 
the RISE/RIDE studies. 
Given the rarity of these events, this study will not be powered to discern 
significant differences between the two comparison groups in the incidence in 
severe adverse events.  As in any study, conclusions regarding the incidence 
of rare adverse events will not be able to be definitively determined in this 
study. 
All adverse events will be reported to by the investigator and/or designee to 
the principal investigator and to the IRB. 
 
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 
 


 
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30 subjects from approximately 1 site in the United States will be enrolled.   Subjects 
will be recruited through clinics at the Cole Eye Institute, Cleveland OH.  Eligible 
subjects will be administered and provided with a copy of informed consent.  (See 
Appendix A, the study flow chart, for screening assessments).  Fellow eyes that 
develop DME during the study period or have DME at study entry will be treated with 
ranibizumab at investigator discretion.  Genentech will supply drug for the nonstudy 
eye.  In the event that both eyes are eligible at study entry, the eye with more 
significant macular edema as defined by the central foveal thickness will be the study 
eye.  
 
 
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 > 18 years 
 ETDRS best-corrected visual acuity of 20/25 to 20/320 in the study eye 
 Willing, committed, and able to return for ALL clinic visits and complete all study 
related procedures 
 At least 6 previous bevacizumab injections for diabetic macular edema in the last 
12 months. 
 At least 2 bevacizumab injections within 10 weeks and the most recent 
bevacizumab injection within 6 weeks of baseline study visits 
 Persistent foveal-involving diabetic macular edema based on presence of 
intraretinal and/or subretinal fluid by SDOCT in the foveal center at study entry 
 
4.1.3 Exclusion Criteria 
 
Subjects who meet any of the following criteria will be excluded from this study:  
 
 Pregnancy (positive pregnancy test) or lactation   
 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. 


 
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 Intravitreal steroid or periocular steroid treatment within 3 months of study 
entry 
 Focal/grid laser photocoagulation treatment within 3 months of study entry 
 Panretinal photocoagulation treatment within 3 months of study entry 
 Prior vitrectomy in the study eye 
 History of retinal detachment in the study eye 
 Prior trabeculectomy or other filtration surgery in the study eye 
 Active intraocular inflammation in either eye 
 Active ocular or periocular infection in either eye 
 Active scleritis or epicscleritis in either eye 
 History of any other retinal vascular disease (e.g., retinal vein occlusion, 
retinal artery occlusion) 
 Coexistent retinal disease other than diabetic retinopathy (e.g., AMD, 
inherited retinal disease) 
 Intraocular surgery within 3 months of study entry. 
 History of corneal transplant or corneal dystrophy 
 Significant media opacities in study eye which may interfere with visual 
acuity 
 Participation as a subject in any clinical study within 3 months of study 
entry. 
 History of allergy to topical iodine 
 Any other condition that the investigator believes would pose a 
significant hazard to the subject if the investigational therapy were 
initiated 
 Participation in another simultaneous medical investigation or trial 
 


 
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4.2 
METHOD OF TREATMENT ASSIGNMENT 
Randomization to the two treatment groups will be utilized.  The study is not 
masked.   
 
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 single-use vial is designed to deliver 0.05 mL of 6 mg/mL 
ranibizumab aqueous solution with 10 mM histidine HCI, 10%, -trehalose dihydrate, 
and 0.01% polysorbate 20, pH 5.5.  The results in the delivery of a 0.3 mg dose of 
ranbizumab.  Each vial contains no preservative and is suitable for single use only. 
Further details and molecule characterization will be included in the Investigator 
Brochure. 
 
4.3.2 Dosage, Administration, and Storage 
a. Dosage 
Subjects will be randomized to two equal size treatment groups. The first 
group will be treated with 0.3 mg ranbizumab monthly for the duration of 
the study.  The second group will be treated with 0.3 mg monthly for the 
first three months and will subsequently be treated with 0.3 mg on a “treat-
and-extend” protocol (as outlined in 4.3.2b).    
b. Administration 
Group 1 will undergo monthly intravitreal injections of 0.3 mg ranibizumab 
administered 30 days (+/- 7 days) following the last treatment for 12 
months.  Injections will be performed with sterile technique as outlined in 
appendix B.   
Group 2 will be assigned to a “treat-and-extend” protocol.  Eyes will be 
treated with 3 loading doses at 30-day (+/- 7 days) intervals.  After the third 
loading dose, the follow-up interval is determined with an OCT-based 
protocol: 
 Criterion A: If the central subfield thickness is less than or equal to 
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subretinal fluid on the macular cube, the follow-up interval is 
increased by 2 weeks (+/- 7 days) at each visit [to a maximum 
interval of 12 weeks (+/- 7 days)].  The eye receives an intravitreal 
ranibizumab injection at every visit.   
 Criterion B:  If on subsequent follow-up visits, the thickness 
increases above 300 microns or there is recurrence of fluid with 
thickness above 300 microns, the interval is reduced by 2 weeks (+/- 
7 days) (to a minimum interval of 4 weeks).   Designated visits will 
also occur at 6 months and 12 months for visual acuity, ocular 
examination, FA, and OCT.  No treatment will occur at these visits 
unless the time coincides with the scheduled “treat-and-extend” visit. 
 Criterion C: Rescue criteria – If on subsequent follow-up visits, a 
patient loses > 15 letters with associated recurrence of fluid or 
central subfield thickness above 300 microns, the dosing interval will 
be immediately reduced to 4 weeks (+/- 7 days) for the next follow-
up visit and for the residual duration of the study. 
 Criterion D:  Intervals following recurrence of fluid.  If criterion B is 
met at any time, the patient will be reduced to a dosing interval as 
dictated above that maintains a central subfield thickness less than 
or equal to 300 microns or a complete absence of intraretinal or 
subretinal fluid on the macular cube.  Once criterion A is met the 
dosing interval is again extended as outlined.  If during a second 
extension period, criterion B is met, the patient is maintained at the 
dosing interval (less than where the second recurrence occurred) 
that maintains a central subfield thickness less than or equal to 300 
microns or a complete absence of intraretinal or subretinal fluid on 
the macular cube for the rest of the study without further extension 
attempts. 
All treatments will be administered at Cole Eye Institute at the Cleveland 
Clinic. 
 
*See Appendix B for detailed pre-injection procedures. 


 
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c. Storage 
Upon receipt, study drug kits should be refrigerated at 2C - 8C (36F - 46F).  
DO NOT FREEZE.  Do not use beyond the expiration date.  Ranibizumab vials 
should remain refrigerated.  Protect vials from direct light. Store in original 
carton until time of use.  
RANIBIZUMAB 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 
During the study period, no additional intravitreal or periocular pharmacologics 
can be administered, including but not limited to bevacizumab, aflibercept, and 
steroids.  Focal laser photocoagulation is also not permitted during the study 
period.  Panretinal photocoagulation is allowed if an eye develops retinal 
neovascularization, optic disc neovascularization, anterior segment 
neovascularization, and/or vitreous hemorrhage thought to be related to 
neovascularization. 
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 
Screening/Day (–10 Days to Day 0) 
After the patient/subject has provided informed consent, the following information will 
be collected: 
  Inclusion/exclusion 
 
Informed consent documentation 
 
Demographics 
 
Medical history and concurrent illnesses 
 
Concomitant medications 
The following procedures and assessments will be conducted: 
 
ETDRS visual acuity with manifest refraction 
 
Slit lamp examination 


 
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 
Fundus examination 
 
Spectral Domain OCT evaluation 
 
Ultra-widefield fluorescein angiogram  
 
Pulse and blood pressure 
 
Weight 
Treatment Period 
Baseline/Day 0/Month 0 (may occur at same time as screening visit) 
The following information will be collected: 
 
Inclusion/exclusion 
 
Informed consent documentation 
 
Demographics 
 
Medical history and concurrent illnesses 
 
Concomitant medications 
 
AEs 
The following procedures and assessments will be conducted: 
 
ETDRS visual acuity with manifest refraction 
 
Slit lamp examination 
 
Fundus examination 
 
Spectral Domain OCT evaluation 
 
Intravitreal injection of ranibizumab 
 
Pulse and blood pressure 
Group 1 (Monthly treatment group): Month 1-Month 11 (+/- 7 Days) 
The following information will be collected: 
 
Concomitant medications 
 
AEs 
The following procedures and assessments will be conducted: 
 
ETDRS visual acuity with manifest refraction 
 
Slit lamp examination 
 
Fundus examination 
 
Spectral Domain OCT evaluation 


 
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 
Intravitreal injection of ranibizumab 
 
Ultra-widefield fluorescein angiogram (months 3 and 6)  
 
Pulse and blood pressure 
 
Group 1 (Monthly treatment group):  End of Treatment/Month 12 (+/- 7 
Days)/Early Termination visit 
The following information will be collected: 
 
Concomitant medications 
 
AEs 
The following procedures and assessments will be conducted: 
 
ETDRS visual acuity with manifest refraction 
 
Slit lamp examination 
 
Fundus examination 
 
Spectral Domain OCT evaluation 
 
Ultra-widefield fluorescein angiogram 
 
Pulse and blood pressure 
 
Weight 
Group 2 (Treat-and-extend group): Month 1-Month 2 (+/- 7 Days)  
The following information will be collected: 
 
Concomitant medications 
 
AEs 
The following procedures and assessments will be conducted: 
 
ETDRS visual acuity with manifest refraction 
 
Slit lamp examination 
 
Fundus examination 
 
Spectral Domain OCT evaluation 
 
Intravitreal injection of ranibizumab 
 
Pulse and blood pressure 


 
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Group 2 (Treat-and-extend group): Month 3-Month 11 Follow-up Interval 
Based on OCT criteria as outlined sections 3.1 and 4.3.2b 
The following information will be collected: 
 
Concomitant medications 
 
AEs 
The following procedures and assessments will be conducted: 
 
ETDRS visual acuity with manifest refraction 
 
Slit lamp examination 
 
Fundus examination 
 
Spectral Domain OCT evaluation 
 
Intravitreal injection of ranibizumab 
 
Ultra-widefield fluorescein angiogram [month 3 and 1st visit after week 22 of 
study entry (~ 6 month visit)]  
 
Pulse and blood pressure 
 
Group 2 (Treat-and-extend treatment group):  End of Treatment/Month 12 
(+/- 7 Days)/Early Termination visit 
The following information will be collected: 
 
Concomitant medications 
 
AEs 
The following procedures and assessments will be conducted: 
 
ETDRS visual acuity with manifest refraction 
 
Slit lamp examination 
 
Fundus examination 
 
Spectral Domain OCT evaluation 
 
Ultra-widefield fluorescein angiogram 
 
Pulse and blood pressure 
 
Weight 
 


 
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Unscheduled visit 
The following information will be collected: 
 
Concomitant medications 
 
AEs 
The following procedures and assessments will be conducted: 
 
ETDRS visual acuity with manifest refraction 
 
Slit lamp examination 
 
Fundus examination 
 
Spectral Domain OCT evaluation 
 
Intravitreal injection of ranibizumab (optional based on investigators discretion if 
greater than 4 weeks since last injection) 
 
Pulse and blood pressure 
 
4.5.2 Early Termination Assessments 
Subjects who withdraw from the study prior to completion should return for an 
early termination evaluation 30 days ( 7 days) following the last injection/study 
visit 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 
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 
condition.  The Cole Eye Institute/Cleveland Clinic or Justis P. Ehlers, MD 
(Principal Investigator) 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. 


 
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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 anti-VEGF therapy other than ranibizumab in the study eye, 
unless as a part of the prospective investigational study design 
 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 Cole Eye Institute/Cleveland Clinic 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 
There is no formal sample size calculation in a pilot study.  As this is a pilot 
study, a sample size of 30 patients is chosen, making sure that it is feasible to 
conduct the study and logistically to complete the study within 2 years.   
If and when the study is planned for a phase II/III randomized control trial, 
appropriate statistical analysis will be determined.  
 


 
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4.8.2 Safety Analyses 
Any adverse events, laboratory assessments, physical examinations, vital 
signs, ocular examinations and measurements from all 30 subjects will be 
utilized to summarize safety data for this pilot study. 
a. Primary Endpoint 
 Incidence and severity of ocular adverse events, as identified by eye 
examination (including visual acuity testing) 
 Incidence and severity of other non-ocular adverse events, as 
identified by physical examination, subject reporting, and changes in 
vital signs 
 
4.8.3 Efficacy Analyses 
 
a. Secondary Endpoints 
 Mean change from baseline in best-corrected visual acuity by the number of 
letters read correctly at months 6 and 12. 
 Mean absolute change from baseline central foveal thickness at months 6 
and 12 as measured by SDOCT (defined as the average thickness within 
the central 1 mm subfield)  
 Proportion of eyes that were anatomically “dry” by SDOCT at months 6 and 
12. 
 Proportion of eyes gaining greater than or equal to 15 letters of vision at 
months 6 and 12. 
 Proportion of eyes losing greater than or equal to 15 letters of vision at 
months 6 and 12. 
 Proportion eyes with 20/40 or better best-corrected visual acuity at months 
6 and 12. 
 Comparison of angiography leakage from baseline to months 3, 6, and 12. 
 Comparison of peripheral nonperfusion from baseline to months 3, 6, and 
12. 
 Comparison of previous anatomic anti-VEGF response to month 3, 
month 6, and month 12 anatomic response. 
 Comparison of previous functional anti-VEGF response to month 3, 
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  
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 
An interim analysis is planned at 6 months.  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.     
 
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, 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 
DME 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 intravitreal injections). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 


 
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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. 
 


 
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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. 
 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 30 days 
following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier.  
 
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 ranibizumab (see following guidance), and actions taken. 


 
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To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
 
Yes 
 
There is a plausible temporal relationship between the onset of the AE and 
administration of ranibizumab, 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 ranibizumab; and/or the AE abates or resolves 
upon discontinuation of the ranibizumab or dose reduction and, if applicable, 
reappears upon re-challenge. 
 
No 
 
Evidence exists that the AE has an etiology other than from ranibizumab (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to ranibizumab 
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.   
Ophthalmologic evaluations will include slitlamp examination, dilated binocular 
indirect high-magnification ophthalmoscopy, measurements of BCVA and 
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widefield fluorescein angiography if at appropriate visit (See Section 4.5 for a 
detailed description of the study assessments.) 
5.5 
VITAL SIGNS 
Pulse and blood pressure will be measured at protocol-specified study visits 
(see Section 4.5).   
 
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. 


 
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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 
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 
60 days after the last dose of study drug, a report should be completed and 


 
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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 ranibizumab should be reported as an SAE. 
f. 
Post-Study Adverse Events 
If the investigator should become aware of an SAE occurring after a subject has 
completed or discontinued study participating if attributed to ranibizumab exposure, 
including, 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 ranibizumab Events of Special Interest are:  
 Endophthalmitis  
 Intraocular inflammation (including vitritis and uveitis)  
 Cataract (Traumatic)  
 Increased IOP 
 ATEs including stroke 
 Retinal Pigment Epithelium Tear  
 Retinal Detachment   
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: 


 
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(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 ranibizumab 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 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 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. 
 
. 
 
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, 


 
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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) 
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  
 
5.6.5 Additional Reporting Requirements for IND Holders 
 
For Investigator-Sponsored IND Studies, some additional reporting requirements for 
the FDA apply in accordance with the guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports according to the following 
guidance and timelines: 
7 Calendar Day Telephone or Fax Report: 
 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to 
the use of ranibizumab. An unexpected adverse event is one that is not already 
described in the ranibizumab Investigator Brochure. Such reports are to be 
telephoned or faxed to the FDA and Genentech within 7 calendar days of first learning 
of the event. 
15 Calendar Day Written Report 
 
The Investigator is also required to notify the FDA and all participating investigators, in 
a written IND Safety Report, of any serious, unexpected AE that is considered 
reasonably or possibly related to the use of ranibizumab. An unexpected adverse 
event is one that is not already described in the ranibizumab investigator brochure. 


 
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Written IND Safety reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32. All safety reports previously filed by the investigator 
with the IND concerning similar events should be analyzed and the significance of the 
new report in light of the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA, Genentech, and all participating investigators within 15 calendar days of first 
learning of the event. The FDA prefers these reports on a Medwatch 3500 form, but 
alternative formats are acceptable (e.g., summary letter). 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must 
also be faxed to Genentech Drug Safety: 
Fax: (650) 225-4682 or (650) 225-5288 
 
And to the Site IRB: 
Cleveland Clinic IRB 
9500 Euclid Ave 
Cleveland, OH 44195 
Phone 216.444.2924 
 
For questions related to safety reporting, please contact Genentech Drug 
Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-5288 
 


 
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IND Annual Reports 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. Copies of such reports should be faxed to Genentech Drug 
Safety: 
 
Fax: (650) 225-4682 or (650) 225-5288 
 
 
Study Close-Out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). 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: 
 
 


 
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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 
 
Principal Investigator 
 
Site Name 
 
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 


 
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6.0 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file with 
Cole Eye Institute/Cleveland Clinic 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 Cole 
Eye Institute/Cleveland Clinic, 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 Cole Eye Institute/Cleveland 
Clinic 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) 


 
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 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. 


 
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 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 Cole Eye Institute/Cleveland Clinic 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 


 
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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 Cole Eye Institute/Cleveland CLinic (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. 


 
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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 
Any study report submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. This includes all IND annual reports and the Clinical 
Study Report (final study report). Additionally, any literature articles that are a 
result of the study should be sent to Genentech. Copies of such reports should 
be faxed to the assigned Clinical Operations contact for the study: 
 
Lucentis IST Program Fax:  1-866-551-1893 
: 
 
 


 
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REFERENCES: 
 
1. 
Wessel MM, Nair N, Aaker GD, Ehrlich JR, D'Amico DJ, Kiss S. Peripheral retinal 
ischaemia, as evaluated by ultra-widefield fluorescein angiography, is associated with 
diabetic macular oedema. The British journal of ophthalmology 2012;96:694-8. 
2. 
Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy 
Study report number 1. Early Treatment Diabetic Retinopathy Study research group. 
Archives of ophthalmology 1985;103:1796-806. 
3. 
Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trial 
comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic 
macular edema. Archives of ophthalmology 2009;127:245-51. 
4. 
Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema 
with prompt versus deferred laser treatment: three-year randomized trial results. 
Ophthalmology 2012;119:2312-8. 
5. 
Boyer DS, Faber D, Gupta S, et al. Dexamethasone intravitreal implant for treatment of 
diabetic macular edema in vitrectomized patients. Retina 2011;31:915-23. 
6. 
Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone 
acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic 
macular edema. Ophthalmology 2012;119:2125-32. 
7. 
Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of 
intravitreal bevacizumab or laser therapy in the management of diabetic macular 
edema (BOLT study) 12-month data: report 2. Ophthalmology 2010;117:1078-1086 e2. 
8. 
Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized 
controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management 
of diabetic macular edema: 24-month data: report 3. Archives of ophthalmology 
2012;130:972-9. 
9. 
Do DV, Schmidt-Erfurth U, Gonzalez VH, et al. The DA VINCI Study: phase 2 primary 
results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology 
2011;118:1819-26. 


 
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10. 
Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: 
results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 
2012;119:789-801. 
11. 
Do DV, Nguyen QD, Khwaja AA, et al. Ranibizumab for Edema of the Macula in 
Diabetes Study: 3-Year Outcomes and the Need for Prolonged Frequent Treatment. 
Archives of ophthalmology 2012:1-7. 
 


 
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APPENDIX A 
Study Flowchart  
Group 1:  Monthly Treatment Group 
 
 
Pretreatment 
Assessments During Treatment (Months)—visit 30 days (+/- 7 days) after 
last treatment 
Follow-Up Assessments 
 
Screen* 
0* 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
End of 
Study Month 
12 
Unscheduled 
Visit 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history   
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
(pulse/BP)   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fundus Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ETDRS Manifest 
Refraction/Complete 
eye exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SDOCT both eyes  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intravitreal 
Ranibizumab  
Injection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X** 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fluorescein 
Angiography 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
* Screening and visit at month zero may occur on the same day.  ** If treatment criteria met as outlined and at 
least 4 weeks has passed since the last injection. 
 


 
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Group 2:  Treat and Extend Group 
 
 
Pretreatment 
Assessments During Treatment (Months) —
visit 30 days (+/- 7 days) after last treatment 
Follow-Up Assessments 
 
Screen* 
0* 
1 
2 
Month 3-11, timing per T 
& E protocol 
 
 
End of Study 
Month 12 
Unscheduled 
Follow-up 
Visit 
Informed consent 
X 
X 
 
 
 
 
 
Demographic data 
X 
X 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
Vital signs 
(pulse/BP) 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
 
X 
 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Exam 
X 
X 
X 
X 
X 
X 
X 
Fundus 
Examination 
X 
X 
X 
X 
X 
X 
X 
ETDRS Manifest 
Refraction/Comple
te eye exam 
X 
X 
X 
X 
X 
X 
X 
SDOCT both eyes 
X 
X 
X 
X 
X 
X 
X 
Intravitreal 
Ranibizumab  
Injection 
 
X 
X 
X 
X 
 
X*** 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
Fluorescein 
Angiography 
X 
 
 
 
[X]** 
X 
 
* Screening and visit at month zero may occur on the same day.  ** Angiography to be performed at month 3 
visit and at the first visit after week 22 (~ 6 month visit). *** If treatment criteria met as outlined for group 2 
and at least 4 weeks have passed since last injection.  T & E: Treat and Extend 
 
 
 
 
 
 
 


 
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APPENDIX B 
Pre-Injection Procedures for All Subjects 
 
In order 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.  Intravitreal injection procedures will be 
performed in accordance with standard injection procedures at the Cleveland Clinic. 
The intravitreal injection procedure will be carried out under controlled aseptic conditions, 
which include the use of sterile gloves, and a sterile eyelid speculum (or equivalent). 
Adequate anesthesia and a broad-spectrum microbicide (e.g., betadine) should be given 
prior to the injection.  


 
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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, Cleveland Clinic 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 Cleveland Clinic 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 Cleveland Clinic 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 Cleveland Clinic  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.


 
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Appendix D: Quantitative Assessment of Ultra-widefield Angiographic Features in 
Diabetic Macular Edema Addendum 
 
Examples of quantitative segmentation of leakage and ischemia in ultra-widefield 
angiography.  Quality permitting, UWFA obtained during study will be assessed for 
quantitative changes.   
 
Figure 1:  Diabetic macular edema and proliferative diabetic retinopathy with automated 
identification of retinal vascular leakage (green).  Longitudinal assessment following anti-
VEGF treatment.  Areas of segmentation (e.g., green) able to be quantified in absolute or 
relative fashions for area. 
 
 
Figure 2: Diabetic macular edema and proliferative diabetic retinopathy with automated 
identification of neovascular leakage (yellow), ischemia (blue) and retinal vascular leakage 
(green).  Longitudinal assessment following anti-VEGF treatment.  Areas of segmentation 
(e.g., green, yellow, blue) able to be quantified in absolute or relative fashions for area. 


 
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Appendix E: Pre-Ranibizumab Assessment of Anti-VEGF Therapeutic Response. 
 As part of the screening process for REACT, the medical records are reviewed for prior 
treatment, medical history, and ophthalmic history information for assessment of inclusion 
and exclusion criteria.   The same medical record will be reviewed for specific data on 
functional (visual acuity) and anatomic (OCT) data on response to bevacizumab prior to 
exposure to ranibizumab in the trial.  This will be performed in a retrospective fashion 
without any additional contact with study subjects or study interventions.    Overall 
response to therapy as well as stratification to ranibizumab response will be assessed 
(e.g., dramatic responder vs nonresponder). Subjects would also be evaluated in the 
context of their bevacizumab response (nonresponder vs incomplete responder vs 
tachyphylaxis). 
 
