Clinical trial NCT01934556
Conditions: Diabetic Macular Edema
Sponsor: Palmetto Retina Center, LLC
Start date: 2013-11-01; Completion date: 2018-04-01
Enrollment: 150 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The purpose of this research study is to determine if a "Treat and Extend" regimen (increasing the time between visits when the disease is stable and not getting worse) of Ranibizumab 0.3 mg injections inside the eye is safe and effective at treating patients with swelling of the retina from diabetes.

Detailed description:
This research study will compare the visual outcomes between a group of patients who are treated with monthly injections of Ranibizumab 0.3 mg and two groups of patients who are treated with the "Treat and Extend" regimen. One of the "Treat and Extend" groups will also receive laser therapy to determine if this has any additional beneficial effects.

Arms: arm 1: Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. arm 2: (60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is \> 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. arm 3: (60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is \> 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.
Interventions: intervention 1: Ranibizumab 0.3 mg intravitreal injection intervention 2: Guided Laser Photocoagulation
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
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PROTOCOL 
STUDY TITLE: 
A phase I/II, open-label, multicenter, 
randomized, controlled study of the safety, 
tolerability and efficacy of intravitreal injections 
of 0.3 mg ranibizumab given monthly compared 
to a Treat and Extend protocol, with and without 
laser photocoagulation, in patients with Diabetic 
Macular Edema (T-REX-DME) 
STUDY DRUG 
Recombinant humanized anti-VEGF 
monoclonal antibody fragment (rhuFab V2 
[ranibizumab]) 
SPONSOR 
Palmetto Retina Center 
124 Sunset Court 
West Columbia, SC 29169 
IND: 
119146 
INVESTIGATOR 
John F. Payne, MD 
SUB-
INVESTIGATORS 
David M. Brown, MD 
Charles C. Wykoff, PhD, MD  
David Boyer, MD 
W. Lloyd Clark, MD 
DATE FINAL: 
June 23, 2015 


 
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TABLE OF CONTENTS 
 
                                
1. 
BACKGROUND ...........................................................................................  
 
1.1 
Pathophysiology ................................................................................  
 
1.2 
Treatment ..........................................................................................  
 
1.3 
Ranibizumab .....................................................................................  
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 ...............................................  
 
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 .................................................................  
 
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 .................................................................................  
 


 
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5.2 
Serious Adverse Events ....................................................................  
5.3 
Methods and Timing for Assessing and Recording Safety Variables  
5.4 
Procedures for Eliciting, Recording, and Reporting Adverse Events .  
 
5.4.1 
Eliciting Adverse Events ......................................................  
 
5.4.2 
Specific Instructions for Recording Adverse Events.............  
 
5.4.3 
Med Watch 3500A Reporting Guidelines …………………… 
 
5.4.4 
Follow-up Information ..........................................................  
 
5.4.5 
Additional Reporting Requirements for IND Holders 
 
 
5.4.6  
Safety Reporting Fax Cover Sheet ......................................  
 
 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 Closeout ..................................................................................  
 
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 
 Diabetes mellitus continues to be a tremendous health burden in 
America.  In 2007, the prevalence of diabetes was estimated to 23.6 
million people, or 7.8% of the US population (Center for Disease Control 
and Prevention, 2007).  Diabetic retinopathy is the leading cause of 
blindness among working age adults, accounting for 8% of all legal 
blindness (Klein and Klein, 1995; Yau et al, 2012). During the first two 
decades with the disease, nearly all of those with type 1 diabetes and > 
60% of those with type 2 diabetes have some degree of retinopathy 
(Fong et al, 2003).  The International Diabetes Federation estimates that 
285 million individuals worldwide have diabetes mellitus and that 
approximately 14% of this group has diabetic macular edema 
(International Diabetes Federation; 2012). 
 
 
The risk factors for retinopathy progression of retinopathy are not 
completely understood.  Age, race, and duration of diabetes all appear 
to play a role.  Other factors, such as poor glycemic and blood pressure 
control, are associated with retinopathy progression as well (ACCORD 
Eye Study Group, 2010).  
  
Three forms of retinopathy are commonly recognized in association with all 
forms of diabetes mellitus:  1) non-proliferative diabetic retinopathy (NPDR), 
2) PDR, and 3) DME. 
NPDR is characterized by ophthalmoscopically visible abnormalities that 
include microaneurysms, intraretinal hemorrhages, exudates, retinal nerve fiber 
layer infarcts called cotton wool spots, and, in more severe cases, venous 
beading and intraretinal microvascular abnormalities.  Over time, NPDR may 
progress to more severe PDR, the hallmark of which is neovascularization on 
the surface of the retina, optic disc, iris, or anterior chamber angle.  PDR is 
associated with a high risk of visual morbidity arising from vitreous hemorrhage, 
traction retinal detachment, and neovascular glaucoma (Diabetic Retinopathy 
Study [DRS] Research Group 1978). 
 
DME is characterized by swelling of the central part of the retina, or the macula, 
that is responsible for high-resolution vision.  It is not uncommon for DME to co-
exist with NPDR or PDR. When the area of swelling is located more than 
one disc diameter (approximately 1500 m) away from the center of the fovea, 
the swelling constitutes a low threat to visual acuity (VA) and is regarded as 
nonclinically significant macular edema (Early Treatment Diabetic Retinopathy 
Study [ETDRS] Research Group 1985).  When the DME involves the foveal 
center, vision is often compromised.  Macular edema that involves the fovea or 
is at high risk of doing so is referred as clinically significant macular edema 
(CSME) (ETDRS Research Group, 1985).  The mechanisms by which DME 
leads to vision loss remain largely unknown. 


 
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It has been fairly well established that DME arises from breakdown of the 
blood-retinal barrier, which leads to an abnormal accumulation of fluid and 
macromolecules within the layers of the retina.  Early histologic findings include 
capillary basement membrane thickening, loss of pericytes, and loss of 
endothelial cells.  Subsequent formation of microaneurysms, breakdown of the 
blood-retinal barrier, and consequent vascular leakage result in the 
pathogenesis of DME (Ho et al, 2012).  The disruption of the blood-retinal 
barrier is thought to be largely due to compromise and increased permeability 
of the retinal vascular endothelium.  The degree of retinal swelling is 
determined by Starling’s law, which describes fluid movement as the outcome 
of the balance between hydrostatic and oncotic pressures in tissues and 
intravascular compartments.  
 
DME may either occur in a focal area due to leakage from microaneurysms or 
in a diffuse fashion from breakdown of the blood-retinal barrier from the walls of 
a compromised capillary bed.  The technique of focal laser photocoagulation, 
which was first described in the ETDRS protocol, results in closure of the 
leaking microaneurysms and cessation of the leakage.  The ETDRS protocol 
also described a grid pattern of laser photocoagulation for treatment of diffuse 
leakage.  The mechanism of action of this therapy remains unclear.  
 
 
1.2 
TREATMENT OF DIABETIC MACULAR EDEMA 
The current standard of care of DME continues to change.  Although focal laser 
photocoagulation plays a significant role in the management of patients with 
DME, its effect is often transient and inadequate.  Fewer than 15% of patients 
gain more than three lines of best-corrected visual acuity at 3 years, whereas > 
15% sustain moderate vision loss of more than three lines.  Focal laser is less 
effective in cases of diffuse macular edema.  Photocoagulation is a destructive 
therapy and can cause symptomatic paracentral scotomas, some of which can 
be disabling after multiple treatments.  Vitrectomy is often reserved for the most 
refractory cases of DME and is associated with vitreous traction and bleeding.  
It also carries surgical risks (cataract formation, retinal detachment, and 
endophthalmitis) and has not been validated in large randomized studies.  
Many recent studies have shown promising visual results of intravitreal 
injections of inhibitors of vascular endothelial growth factor (VEGF).  There is 
substantial evidence that suggests that these medications are superior to focal 
laser photocoagulation.  However, many of these studies were designed to 
treat patients on a monthly basis.  Because many of the patients with DME are 
young and because these injections are not a cure for the disease, the 
treatment burden can be substantial.   
 
1.2.1 GLUCOSE CONTROL 
 
 


 
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Although glucose control does not have a direct effect on macular edema, it 
plays a role in the management of diabetic retinopathy as a primary and 
secondary prevention strategy.  Improving blood glucose and blood pressure 
has been shown to slow the progression of retinopathy (DCCT Research 
Group, 1993; UKPDS Research Group, 1998a, 1998b).  After 5 years of follow-
up, there was a significant reduction in the risk of retinopathy progression by 
76% in those being treated with intensive insulin therapy when compared to 
those with conventional insulin therapy.  In the secondary intervention cohort, 
the progression of retinopathy was reduced by 54% in the intensive therapy 
group during the entire study period compared to those with conventional 
therapy.  Additionally, the need for laser treatment was reduced by 56% in 
those in the intensive insulin therapy group.  It should be noted that there was a 
higher frequency of “early worsening”, or progression of retinopathy after a 
significant reduction in blood glucose levels, in the intensive therapy group.  At 
1 year, early worsening occurred in 13% of patients in the intensive therapy 
group compared to 8% in the conventional group.  However, the large long-
term risk reduction with intensive treatment was such that outcomes in the 
intensively treated subjects who had early worsening were similar to or more 
favorable than outcomes in the conventionally treated subjects who had not.  
With respect to macular edema, intensive therapy reduced the risk of onset of 
DME by 23% compared to conventional treatment. 
 
1.2.2 LASER PHOTOCOAGULATION 
 
Up until the last few years, laser photocoagulation remains the only therapy 
demonstrated to confer a clear-cut clinical benefit for any patients with DME 
(ETDRS Research Group 1985).  Although laser photocoagulation does not 
restore vision on average, and relatively few patients gain clinically meaningful 
vision, it does slow the progression of moderate vision loss. In the ETDRS, 
subjects with DME assigned to early macular laser photocoagulation were half 
as likely to lose 15 or more letters on the ETDRS visual chart at 3 years than 
those who were not (12% vs. 25%). For those with CSME involving the foveal 
center, subjects assigned to receive early macular laser photocoagulation were 
also less likely to lose 15 or more letters at 3 years than those who were not 
(13% vs. 33%) (ETDRS Research Group 1987). In a more recent study 
comparing laser photocoagulation with intravitreal corticosteroids for DME 
involving the fovea, laser-treated patients gained a mean of + 1 ETDRS letter 
from baseline to 2 years, and + 5 ETDRS letters from baseline to 3 years. At 2 
years, 14% of laser-treated patients had lost 15 or more ETDRS letters, and 
18% had gained 15 or more ETDRS letters. Among patients who completed 3 
years from study baseline, 30% of patients treated with laser photocoagulation 
improved by 15 or more ETDRS letters, and 9% lost 15 or more ETDRS letters 
(Diabetic Retinopathy Clinical Network, 
2008 and 2009). Although photocoagulation for center involving CSME is a 
significant achievement in the management of diabetic retinopathy, laser 
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at the end of 3 years. Moreover, given that 69% of subjects with CSME in the 
ETDRS group had center involvement at presentation (ETDRS Research 
Group 1987), the unmet clinical need for better treatment of center involving 
CSME is significant. 
 
1.2.3 INTRAVITREAL CORTICOSTEROIDS 
 
Several non-randomized case series provided early evidence of the therapeutic 
effect from intravitreal corticosteroids for the management of DME.  The biologic 
basis for the suggested beneficial effect most likely derives from the ability of 
corticosteroids to inhibit VEGF gene expression (Nauck et al, 1998).  In a study 
of 26 eyes of 20 subjects by Jones an colleagues, a single 25 mg intravitreal 
injection of triamcinolone acetonide (TA; Kenalog) was associated with a 
significant visual improvement (P < 0.001) from 20/165 at baseline to 20/105 at 
six months follow-up.  In comparison, 16 subjects observed in a “control group” 
that received grid laser photocoagulation showed no improvement in vision. In a 
separate uncontrolled study of 16 eyes with CSME that did not respond to laser 
photocoagulation, a 4-mg intravitreal injection of TA resulted in mean VA 
improvement of 2.4, 2.4, and 1.3 Snellen lines and reduction of central macular 
thickness by 55%, 57%, and 38% measured at the 1, 3, and 6-month follow-up 
intervals, respectively (Martidis et al. 2002).  In these and other studies with TA, 
the beneficial effects on retinal edema and vision were accompanied by 
elevated intraocular pressure (IOP) and cataract progression.  Furthermore, 
optic nerve damage can occur if IOP remains persistently elevated. 
 
To better understand the risk-benefit profile of steroids for DME, a larger study 
(693 subjects, 840 eyes) was undertaken by the Diabetic Retinopathy Clinical 
Research Network (2008, 2009) comparing repeat administration of two 
dosages 
(1 mg or 4 mg) of intravitreal, preservative-free TA with focal/grid laser 
photocoagulation. Although mean visual acuity was better at 4 months in the 
4 mg TA-treated group, by 1 year, no difference was observed in visual acuity 
among the treated groups, and at 2 and 3 years, mean VA improvement was 
better 
in the laser-treated group. These results were not solely the result of increased 
rates of cataract formation in the TA groups. Thus, over follow-up periods of 2 
and 
3 years, focal/grid laser photocoagulation was both more effective and had 
fewer 
side effects than TA in management of DME involving the fovea. Additionally, 
results from a separate randomized study conducted by the Diabetic 
Retinopathy Clinical Research Network comparing ranibizumab plus prompt or 
deferred focal laser, triamcinolone plus prompt laser, and prompt focal/grid laser 
alone showed that triamcinolone plus laser was no more effective than laser 
alone in improving BCVA through at least 1 year (DRCR.net, Ophthalmology 
2010). In a subset of subjects who were pseudophakic, intravitreal triamcinolone 


 
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plus laser appeared more effective than laser alone, but was frequently 
associated with intraocular pressure elevation. 
 
1.2.4 VITRECTOMY 
 
In a subset of patients with DME, vitreous traction leads to a mechanical 
distortion of retinal anatomy.  These mechanical vector forces on the retina may 
cause and exacerbate macular edema.  Cases such as these, in which  
mechanical traction complicates the pathology of macular edema, are less 
responsive to laser therapy and presumably intravitreal corticosteroids  
Vitrectomy may play a role in this setting to prevent severe vision loss  Some 
studies of subjects with DME have reported DME resolution in 45-82% of eyes, 
and visual improvement by two or more lines in 49-86% if subjects (van 
Effenterre et al, 1993; Tachi and Ogino, 1996; Pendergast et al, 2000). 
 
1.2.5. PEGAPTANIB SODIUM INJECTION 
 
Results from an experimental anti-VEGF therapy, pegaptanib sodium injection 
(Macugen), showed a biologic effect in DME.  Pegaptanib is an inhibitory 
aptamer, currently approved for the treatment of neovascular (wet) age-related 
macular degeneration (AMD). It is typically delivered as an intravitreal injection 
every 6 weeks.  Positive results from a phase 3, multicenter, randomized study 
(n = 260) of intravitreal pegaptanib compared with sham injection for DME have 
been published (Sultan et al, 2011).  This clinical trial compared 0.3 mg of 
intravitreal pegaptanib every 6 weeks with a sham injection.  Patients could 
receive macular photocoagulation in the study after week 18 based on ETDRS 
criteria.  No safety issues were identified in this study and pegaptanib was 
superior to sham injection with respect to 2-line visual acuity gains at month 12.  
37% of those treated with pegaptanib demonstrated a 2-line visual benefit 
compared to 20% in the sham injection group (p = 0.0047).  Mean BCVA at 
month 12 was +5.1 letters (pegaptanib) compared with +1.2 letters (sham; p < 
0.05).   
 
1.2.6   BEVACIZUMAB 
 
Bevacizumab (marketed under the trade name Avastin) is an anti-VEGF 
monoclonal antibody with similar mechanism of action to ranibizumab.  Avastin 
is approved for the systemic treatment of colorectal cancer in combination with 
5-fluorouracil-based chemotherapy, and for the first-line treatment of metastatic 
non-squamous, non-small cell lung cancer in combination with carboplatin and 
paclitaxel.  The significant unmet need for better therapies in DME has caused 
a surge in investigations (primarily case reports and case series) of off-label 
intravitreal use of bevacizumab as salvage and primary therapy in DME. 
 
While many of the studies are small and uncontrolled, they suggest evidence of 
biologic activity through effect on macular anatomy and visual function.  Most 


 
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recently, the level II Bevacizumab or Laser Therapy (BOLT) study reported 2-
year results comparing intravitreal bevacizumab 1.25 mg versus focal macular 
laser treatment for DME in 80 subjects (Rajendram et al, 2012 epub ahead of 
print).  Median gain in BCVA was superior for intravitreal bevacizumab (+9 
letters) compared with macular laser treatment (+2.5 letters; p = 0.005).  Mean 
central macular thickness reduction was slightly greater, but not statistically 
significant, in the intravitreal bevacizumab group at 24 months (-146 m) 
versus the macular laser treatment group (-118 m; p = 0.62).  
 
1.2.7  AFLIBERCEPT 
 
Aflibercept (Eylea), also known as VEGF Trap-Eye (VTE), has been approved 
for treatment of DME.  It is currently approved for treatment of neovascular 
AMD and for macular edema secondary to central retinal vein occlusions as 
well.  The phase II DA VINCI trial demonstrated the efficacy of VTE compared 
with macular laser for the treatment of DME.  In this level II study, 221 patients 
with CSME involving the central macula were randomized to 1 of 5 treatment 
protocols.  At 24 weeks, treatment groups with VTE showed visual acuity 
benefits between +8.5 and +11.4 letters compared to +2.5 letters in the laser 
group (p < 0.0085).  Adverse events reported were consistent with other 
intravitreal treatment agents. 
 
1.3 
RANIBIZUMAB AND DIABETIC MACULAR EDEMA 
The rationale for VEGF inhibition in DME is well established.  DME is 
characterized by a local breakdown of the blood-retinal barrier, resulting in 
vascular leakage through changes in tight junctions, upregulation of intra-
endothelial vesicles, and permeation of retinal vascular endothelial and retinal 
pigment epithelial cells that have undergone degenerative changes (Vinores et 
al, 1999).  It is well established that vascular leakage in patients with diabetic 
retinopathy is promoted by VEGF (Witmer et al, 2003).  Intraocular expression 
and levels of VEGF are markedly increased and correlate with the severity and 
degree of retinopathy (Funatsu et al, 2003, 2005, 2006).  VEGF, which is 
upregulated by interluekin-6 (another key diffusible factor in DME), exerts direct 
biologic effect on endothelial cells through intercellular adhesion molecule-1, 
with downstream effects on intraretinal leukostasis, monocyte chemotaxis, 
tight-junction changes, and subsequent blood-retinal barrier breakdown (Cohen 
et al, 1996; Ishida et al, 2003). 
 
Unmet need drives demand for new alternative therapies for DME.  There is 
growing clinical rationale for VEGF inhibition by ranibizumab in the treatment of 
DME.  Limited clinical experience with ranibizumab in DME was first available 
in small, uncontrolled investigator-sponsored trials (ISTs), for which Genentech 
has provided support.  In a series of 10 subjects studied in a Phase I IST 
supported by Genentech, Chun et al (2006) showed that three monthly 
injections of 0.3 mg or 0.5 mg ranibizumab were tolerated by subjects with 
center-involved CSME.  At 3 months, 4 of 10 subjects gained  15 letters, 5 of 


 
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10 subjects gained  10 letters, and 8 of 10 subjects gained  1 letter.  At 
month 3, the 0.5 mg and 0.3 mg ranibizumab groups demonstrated an 
improvement of vision by +7.8 letters and +12 letters, respectively.  Although 
subjects in both dose arms showed improvement in BCVA from baseline, the 
anatomic and functional outcomes were better for the high-dose group. 
 
Multiple level I studies (DRCR, RESTORE, RISE, RIDE) have demonstrated 
the efficacy of intravitreal ranbizumab for the treatment of DME.  Level I data 
from the DRCR Network showed that patients treated with 0.5 mg ranibizumab 
plus prompt laser (n = 187) or deferred laser ( 24 weeks; n = 188) had 
significantly better visual acuity outcomes at the 1 year mark than those treated 
with sham injection plus prompt laser (n = 293).  Mean change in BCVA in the 
ranibizumab groups were +9 letters compared to +3 for the sham injection 
group.  The 2-year results demonstrated similar findings. 
 
The RESTORE trial, as well as the RISE and RIDE trials, supported the 
indication for ranibizumab for the treatment of DME.  All three of these studies 
showed significant visual gains in the ranibizumab treated groups compared to 
those not treated with ranibizumab. 
 
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). 
 


 
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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 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 recipients 
in ranibizumab.  Intravitreal injections, including those with ranibizumab, have 
been associated with endophthalmitis 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 serious 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 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, 
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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. 
 
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, 
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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 Cohort1. 
 
 
Refer to the Ranibizumab Investigator Brochure or Lucentis® Package Insert 
for  
additional details regarding clinical safety experience with ranibizumab. 
 
2. OBJECTIVES 
This trial will assess the safety, tolerability and efficacy of a treat and extend 
management protocol for DME. Patients will be enrolled into one of three 
treatment groups: (1) monthly intravitreal injections of 0.3 mg ranibizumab 
(Monthly Cohort, 30 eyes); (2) monthly intravitreal injections of 0.3 mg 
ranibizumab for 4 visits, followed by a “TReat and EXtend” protocol based on 
pre-specified criteria of disease activity (T-REX cohort, 60 eyes); (3) monthly 
intravitreal injections of 0.3 mg ranibizumab for 4 visits combined with 
adjunctive GuIded focal LAser macular photocoaulation to microaneurysms at 
week 4 and then every 3 months if leakage is present on fluorescein 
angiography, followed by a treat and extend protocol based on pre-specified 
criteria of disease activity (GILA cohort, 60 eyes).   
 
2.1 Primary Objective 
 Mean change in ETDRS visual acuity at 24 months (week 92 – week 107) from 
Day 0.  
 
2.2 Secondary Objectives 
 Incidence and severity of adverse events (ocular and non-ocular). 
 Total number of intravitreal injections required during each year of the study 
period (week 52, week 104, and week 156). In a separate proof of concept 
analysis, the number of intravitreal injections in the TREX and GILA cohorts 
over the 36-month study period will be compared with that of the other two 
cohorts (p = 0.20). 
 Total number of office visits and imaging studies performed during each year of 
the study period. 
 
 Mean change in central foveal thickness per SD-OCT from randomization to 12 
months (week46 – week 57),randomization to 24 months (week 92 – week 107) 
, and randomization to 36 months (week 156). 
 
 Percentage of eyes gaining or losing 3 lines of vision or more and 1 line of 
vision or more at 6 months (week 22 – week 29),12 months (week 46 – week 


 
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57),18 months (week 70 – week 85),24 months (week 92 – week 107), and 36 
months (week 156) from Day 0.  
 
 Noninferiority comparison (margin of 9 letters) of mean change in ETDRS 
vision from Day 0 to 24 months (week 92 – week 107) between the three study 
groups.   
 
 The percentage of eyes which show progression of proliferative diabetic 
retinopathy requiring panretinal photocoagulation and/or pars plana vitrectomy 
over the 36-month study period. 
 
 The percentage of eyes in the TREX and GILA cohorts who are eligible to 
begin the extension phase after 4 treatment visits. 
 For TREX and GILA Cohorts, the time to achieve a “Secondary or Tertiary 
Baseline” retinal thickness. 
 Percentage of eyes in each cohort that have shown a two-step change 
(increase and decrease) in diabetic retinopathy at 24 months and 36 months 
from day 0. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an open-label, phase I/II trial, which will assess the safety, tolerability 
and efficacy of a treat and extend management protocol for DME.  Eyes which 
meet screening criteria will be enrolled into one of three treatment groups: (1) 
monthly intravitreal injections of 0.3 mg ranibizumab (Monthly Cohort, 30 eyes); 
(2) monthly intravitreal injections of 0.3 mg ranibizumab for 4 visits, followed by 
a “TReat and EXtend” protocol based on pre-specified criteria of disease 
activity (T-REX cohort, 60 eyes); (3) monthly intravitreal injections of 0.3 mg 
ranibizumab for 4 visits combined with adjunctive GuIded focal LAser 
photocoaulation to microaneurysms at week 4 and then every 3 months if 
leakage is present on fluorescein angiography, followed by a treat and extend 
protocol based on pre-specified criteria of disease activity (GILA cohort, 60 
eyes).   
 
 
 
Randomization Scheme: 
 
All eyes which satisfy all inclusion/exclusion criteria will be randomized 1:2:2 
into the Monthly:TREX:GILA Cohorts. 
 
3 Treatment arms: 
1. Monthly Cohort (30 eyes): Monthly intravitreal injections of 0.3 mg 
ranibizumab for 36 months, unless they meet pre-specified criteria for 
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subsequent study visits should be scheduled to occur every 28 (7) 
days relative to the date of the first injection.  Dosing should not occur 
earlier than 21 days after previous treatments.   
Starting at week 104, study eyes will have the opportunity to undergo 
treatment on a pro re nata (PRN) basis.  Thus, eyes who have a central 
subfield thickness (CST) ≤ 325 microns at the week 104 visit, will not be 
given treatment at week 104.  Eyes will continue to be seen every 4 
weeks and will be given an intravitreal injection of ranibizumab 0.3 mg 
only if the CST is > 325 microns.  Eyes will also receive treatment if 
there is a > 5 letter loss due to DME (compared to the vision at week 
104), regardless of thickness on OCT.   
 
Subjects will be evaluated for focal laser treatment at week 116, week 
128, week 140, and week 152.  If the subject has received ≥ 2 
intravitreal injections of ranibizumab within the prior 90 day period, then 
fluorescein angiography will be performed and focal laser treatment will 
be applied to any leaking microaneurysms.  If the patient does not meet 
this criteria for focal laser treatment, then fluorescein angiography and 
focal laser treatment will be deferred and reassessed at the subsequent 
laser evaluation visit. Focal laser treatment and focal laser re-treatment 
will be administered no more than once every 90 days. 
 
Focal laser therapy will be applied to all leaking microaneurysms on 
fluorescein angiography.  Focal laser therapy will not be applied if 
significant macular ischemia is present involving the foveal avascular 
zone (once this has been determined additional fluorescein angiography 
and focal laser treatment planning should not be performed as the 
subject will no longer be eligible for focal laser treatment).  Focal laser 
will also not be applied if treatment is considered too close to the foveal 
avascular zone or to macular edema not related to DME (cystoid 
macular edema, etc.).  If no microaneurysms are present on fluorescein 
angiography, then focal laser therapy should be deferred and 
reassessed with repeat fluorescein angiography at the first visit that 
occurs after 90 days. 
 
2. TREX Cohort (60 eyes): Monthly intravitreal injections of 0.3 mg 
ranibizumab for four (4) visits. If the central foveal thickness is  325 m at the 
fourth visit (Week 12) then the baseline retinal thickness will be recorded, the 
eye will receive 0.3 mg ranibizumab and the study eye will begin the extension 
phase of the study.  For all subsequent visits in the extension phase, 
appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. 
extend, maintain, reduce) will be made based on pre-specified SD-OCT criteria 
(SEE TREATMENT INTERVAL DETERMINATION).  Treatment is rendered at 


 
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every visit, no earlier than 7 days before the target date and no later than 7 
days after the target date, but the time between visits is individualized based on 
each subject’s response to treatment.  Dosing should not occur earlier than 21 
days after previous treatments. 
 
If the central foveal thickness is > 325 m at week 12, the patient will continue 
to receive monthly intravitreal injections of 0.3 mg ranbizumab until the central 
foveal thickness is  325 m.  Once the central foveal thickness is  325 m, 
the study eye will begin the extension phase of the study. 
 
Starting at week 104, study eyes will have the opportunity to undergo 
treatment on a pro re nata (PRN) basis.  Thus, eyes who have a central 
subfield thickness (CST) ≤ 325 microns at the week 104 visit, will not be 
given treatment at week 104.  Starting at week 104, eyes will be seen 
every 4 weeks and will be given an intravitreal injection of ranibizumab 
0.3 mg only if the CST is > 325 microns.  Eyes will also receive 
treatment if there is a > 5 letter loss due to DME (compared to the vision 
at week 104), regardless of thickness on OCT.   
 
Subjects will be evaluated for focal laser treatment at week 116, week 
128, week 140, and week 152.  If the subject has received ≥ 2 
intravitreal injections of ranibizumab within the prior 90 day period, then 
fluorescein angiography will be performed and focal laser treatment will 
be applied to any leaking microaneurysms.  If the patient does not meet 
this criteria for focal laser treatment, then fluorescein angiography and 
focal laser treatment will be deferred and reassessed at the subsequent 
laser evaluation visit. Focal laser treatment and focal laser re-treatment 
will be administered no more than once every 90 days. 
 
Focal laser therapy will be applied to all leaking microaneurysms on 
fluorescein angiography.  Focal laser therapy will not be applied if 
significant macular ischemia is present involving the foveal avascular 
zone (once this has been determined additional fluorescein angiography 
and focal laser treatment planning should not be performed as the 
subject will no longer be eligible for focal laser treatment).  Focal laser 
will also not be applied if treatment is considered too close to the foveal 
avascular zone or to macular edema not related to DME (cystoid 
macular edema, etc.).  If no microaneurysms are present on fluorescein 
angiography, then focal laser therapy should be deferred and 
reassessed with repeat fluorescein angiography at the first visit that 
occurs after 90 days. 
 


 
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3. GILA Cohort (60 eyes): Monthly intravitreal injections of 0.3 mg ranibizumab 
for four visits combined with GuIded LAser (GILA) photocoagulation to all 
microaneurysms in the area of DME at the second visit (Week 4). Fluorescein 
angiography is to be repeated approximately every 3 months (the first visit that 
occurs ≥ 90 days from the preceeding fluorescein angiography visit). Guided 
laser will be repeated at those visits if leakage is present from microaneurysms.  
 
If the central foveal thickness is  325 m at Week 12 then the baseline retinal 
thickness will be recorded, the eye will receive 0.3 mg ranibizumab, and the 
study eye will begin the extension phase of the study.  In the extension phase, 
appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. 
extend, maintain, reduce) will be made based on pre-specified SD-OCT criteria 
(SEE TREATMENT INTERVAL DETERMINATION).  Treatment is rendered at 
every visit, no earlier than 7 days before the target date and no later than 7 
days after the target date, but the time between visits is individualized based on 
each subject’s response to treatment.  Dosing should not occur earlier than 21 
days after previous treatments. 
 
If the central foveal thickness is > 325 m at week 12, then the patient will 
continue to receive monthly intravitreal injections of 0.3 mg ranbizumab and 
possible guided laser photocoagulation, approximately every 3 months until the 
central foveal thickness is  325 m.  Once the central foveal thickness is  325 
m, then the study eye will begin the extension phase of the study. 
 
Starting at week 104, study eyes will have the opportunity to undergo 
treatment on a pro re nata (PRN) basis.  Thus, eyes who have a central 
subfield thickness (CST) ≤ 325 microns at the week 104 visit, will not be 
given treatment at week 104.  Starting at week 104, eyes will be seen 
every 4 weeks and will be given an intravitreal injection of ranibizumab 
0.3 mg only if the CST is > 325 microns.  Eyes will also receive 
treatment if there is a > 5 letter loss due to DME (compared to the vision 
at week 104), regardless of thickness on OCT.   
 
After week 104, subjects will be evaluated for focal laser treatment in 
the same manner as the Monthly and TREX Cohorts.  Subjects will be 
evaluated for focal laser treatment at week 116, week 128, week 140, 
and week 152.  If the subject has received ≥ 2 intravitreal injections of 
ranibizumab within the prior 90 day period, then fluorescein angiography 
will be performed and focal laser treatment will be applied to any leaking 
microaneurysms.  If the patient does not meet this criteria for focal laser 
treatment, then fluorescein angiography and focal laser treatment will be 
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laser treatment and focal laser re-treatment will be administered no 
more than once every 90 days. 
 
Focal laser therapy will be applied to all leaking microaneurysms on 
fluorescein angiography.  Focal laser therapy will not be applied if 
significant macular ischemia is present involving the foveal avascular 
zone (once this has been determined additional fluorescein angiography 
and focal laser treatment planning should not be performed as the 
subject will no longer be eligible for focal laser treatment).  Focal laser 
will also not be applied if treatment is considered too close to the foveal 
avascular zone or to macular edema not related to DME (cystoid 
macular edema, etc.).  If no microaneurysms are present on fluorescein 
angiography, then focal laser therapy should be deferred and 
reassessed with repeat fluorescein angiography at the first visit that 
occurs after 90 days. 
 
 
Baseline Retinal Thickness Measurement for the TREX and GILA Cohorts: 
For eyes which have a central foveal thickness  325 m at week 12, a 
“Primary Baseline” retinal thickness will be defined as the thinnest 
central foveal thickness on SD-OCT over the first four visits of monthly 
treatment.  Eyes which have a central foveal thickness > 325 m at 
week 12 will continue to receive monthly intravitreal injections of 0.3 mg 
ranibizumab until the central foveal thickness is  325 m, at which 
point their “Primary Baseline” retinal thickness will be established.  Eyes 
in the GILA cohort will continue to receive guided laser 
photocoagulation to microaneurysms every 3 months if leakage is 
present on fluorescein angiography. 
If at any point in the study period, the study eye has improved more 
than 20% from the primary baseline thickness for three consecutive 
visits and there is less than 50 microns of variability in central foveal 
thickness between these visits, then a “Secondary Baseline” retinal 
thickness will be established.  This “Secondary Baseline” retinal 
thickness will then be used for treatment interval determinations from 
that point forward. If the study eye has improved more than 20% from 
the secondary baseline thickness for three consecutive visits and there 
is less than 50 microns of variability in central foveal thickness between 
these visits, then a “Tertiary Baseline” retinal thickness will be 
established.  This “Tertiary Baseline” retinal thickness will then be used 
for treatment interval determinations from that point forward.   
 
Treatment Interval Determination For TREX and GILA Cohorts: 


 
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Starting at Week 12, if the central foveal thickness is  325 m, then the 
following re-treatment criteria will be applied at all visits.  Eyes with 
central foveal thickness > 325 m at week 12 will continue to receive 
monthly injections of 0.3 mg ranibizumab until the central foveal 
thickness is  325 m, at which time the following re-treatment criteria 
will be applied at all visits. Eyes in the GILA cohort will continue to 
receive guided laser photocoagulation to microaneurysms every 3 
months if leakage is present on fluorescein angiography.  This treatment 
interval determination will continue up to week 104. 
 
Extend Interval (by 2 weeks): 
1. If the central foveal thickness on SD-OCT is within ≤10% thicker or thinner 
compared to baseline (primary, secondary, or tertiary baseline) retinal 
thickness. 
 
Maintain Interval: 
1. If the central foveal thickness is between >10% thicker and ≤ 20% thicker 
from the baseline retinal thickness (primary, secondary or tertiary baseline) OR 
2. If the central foveal thickness is > 10% thinner from baseline retinal thickness 
(primary, secondary or tertiary baseline). 
 
Reduce Interval (by 2 weeks): 
1. If the central foveal thickness is > 20% thicker from baseline retinal thickness 
(primary, secondary or tertiary baseline). 
 
Reduce Interval to 4 weeks: 
1. If there is a loss of more than 15 letters from best previous ETDRS vision, 
due to DME. 
 
Study eyes which have not met criteria allowing them to extend to greater then 
or equal to 6 weeks for two consecutive visits by the week 52 (hard endpoint) 
visit will receive a series of three intravitreal injections of ranibizumab 0.3 mg 
every 4 weeks regardless of SD-OCT measurement. This series of three 
injections every 4 weeks will begin at the first treatment visit that occurs after 
the 52 week hard endpoint visit.The study eye will resume treatment interval 
determinations based on the pre-specified criteria at the time of the third 
monthly intravitreal injection. 
 
The interval between study injections will not exceed 12 weeks in year 
one of the study.  The interval between study injections can be 
extended to, but not more than, 16 weeks in year two of the study.   
Enrolled subjects will have ETDRS BCVA, complete ophthalmic examination 
and SD-OCT evaluation using Spectralis machines at each visit.  Fluorescein 
angiography will be done in the Monthly and TREX Cohorts at baseline 
(screening visit) and again at week 12, week 52, and week 104 or visits closest 


 
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to.  Fluorescein angiography will be done in the GILA Cohort at baseline 
(screening visit), week 4, and every 90 days or greater (first visit that occurs > 
90 days from previous fluorescein angiogram). See Appendix A for schedule of 
events from screening visit to week 104 and Appendix A.1 for the schedule of 
events between week 108 and week 156. 
 
End-Point Visits 
Subjects will continue to receive study treatments according to the above 
treatment protocol until week 155.  A “Hard End-Point Visit” will occur at week 
52,week 104, and week 156.  A “Biologic End-Point Visit” will occur 4 weeks 
after the previous injection near the 12-month time point (week 46 – week 
57),24-month time point (week 92 – week 107).  Only best corrected visual 
acuity and SD-OCT measurements will be recorded at these endpoint visits.  
No study treatment will be given at these end-point visits, unless the patient has 
a regular study treatment visit that occurs at these time points. 
 
   
Fellow eyes not enrolled into a study group that have DME during the course of 
the study may be treated with standard of care macular laser photocoagulation 
and/or intravitreal injections of 0.3 mg of ranibizumab at the investigator’s 
discretion.  Ranibizumab will be provided by Genentech for treatment of DME in 
the fellow eye. 
 
 
3.2 
Rationale For Study Design 
Diabetic macular edema (DME) is the most common cause of severe vision 
loss in Americans under 60.  However, even mild to moderate vision loss from 
DME is impactful, since it strikes individuals often in the productive periods of 
their lives.  Until now, interventions for diabetic retinopathy have been focused 
on maintaining current visual function or slowing the rate of vision loss. 
 
The RISE and RIDE studies were parallel, phase III, double-masked clinical 
trials designed to evaluate the efficacy and safety of ranibizumab in the 
treatment of DME.  In similarly designed protocols, patients were treated with 
monthly injections of ranibizumab (0.3 mg and 0.5 mg) versus sham monthly 
injections (all arms could receive macular laser photocoagulation from month 3 
if meeting predefined criteria).  The 2-year results demonstrated a statistically 
significant benefit from ranibizumab across numerous parameters, including 
mean change in visual acuity, percent of 10 letter and 15 letter gainers, and 
reduction in retinal thickness by OCT.  Other smaller clinical trials have also 
demonstrated superiority of ranibizumab to laser alone.      
 
Rationale for “Treat and Extend” versus fixed dosing  
RISE and RIDE employed fixed dosing strategies during the entire 3-year 
mandatory treatment period.  Like age-related macular degeneration, the best 
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identified.  However, monthly dosing of ranibizumab is problematic in DME for 
several reasons.  First, compliance is often difficult in this population.  In the 
RISE and RIDE studies, and multiple DRCR.net protocols, dropout rates 
consistently approach 10% per year.  In addition, the natural history of DME 
suggests that long-term treatment will be required.  This is quite different from 
age-related macular degeneration and retinal vein occlusion, where the disease 
activity wanes over time in many patients.   
 
Because of these and other realities, alternatives to chronic, monthly dosing 
need to be explored.  The DRCR Network has employed a “4-2-7” strategy in 
which patients receive 4 mandatory doses, followed by PRN dosing based on 
clinical response.  In this proposal, an initial loading dose of 4 injections is 
proposed because much of the vision gains in RISE and RIDE were attained 
during the first 120 days.  By only extending the interval by 2 weeks at each 
successful visit, it is postulated that the gains achieved early on may be 
maintained without aggressive recurrence.  Once a patient reaches an interval 
that limits the control of disease activity, their recurrence is likely to be mild or 
even subclinical.  At one year, it is likely that there will be a wide variety of 
dosing intervals in the cohort, based on disease activity, addition of panretinal 
photocoagulation, or other factors.  What is unknown is how the visual 
outcomes with a “treat and extend” protocol will compare to the RISE and RIDE 
trials.  
 
Rationale for GuIded LAser photocoagulation 
Since the publication of the Early Treatment Diabetic Retinopathy Study 
(ETDRS), macular laser photocoagulation has been vital in the management of 
DME.  Because of the retina community’s positive experience with macular 
laser, it is likely that many clinicians will utilize some form of combination 
therapy in clinical practice. Recent data published by the Diabetic Retinopathy 
Clinical Research Network’s (DRCR.net) protocol I offers some direction for 
inclusion of laser in this protocol.   Although faithful treatment with ranibizumab 
alone offered the best final visual outcome, the number of injections required at 
long-term follow-up were less in patients that received macular laser sometime 
during their treatment.  In Protocol I, patients who received deferred laser had 
better visual outcomes compared to those receiving laser at entry.  It is felt that 
by treating initially with ranbizumab caused some resolution of the macular 
edema, which allowed for better treatment effect with lower laser power 
settings, thereby minimizing laser-induced scotomas. 
 
A potential drawback of the modified-ETDRS focal laser protocol employed in 
most DME trials is that the laser application is guided manually, which can be 
difficult in a living, moving patient.  Accuracy of treatment delivery is always a 
concern and collateral damage to the neurosensory retina can lead to vision 
loss in some patients.  The navigated laser (NAVILAS) photocoagulator is a 
novel laser delivery system that utilizes a retinal eye-tracking and laser 
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and to provide the ability to localize microaneurysms, which may be difficult to 
target using a traditional slit-lamp laser. Several studies have shown that the 
NAVILAS system is safe and achieves a higher rate of accuracy in 
photocoagulation treatments than standard manual-technique methods (Kozak 
et al, 2012).  Because the NAVILAS photocoagulator uses a camera-based 
system, larger areas of the retina can be visualized, there is less glare artifact, 
and the patient is more comfortable (Kernt et al, 2011).  A further advantage of 
the NAVILAS system is that it allows standardized laser treatment to all 
microanuerysms in the area of DME, which would be beneficial for this study 
and future clinical trial designs.   
 
Summary 
To date, evidence from multiple clinical trials suggests that monthly 
ranibizumab combined with laser sometime during the beginning of therapy 
offers the best long-term clinical outcomes. Although a promising therapy, there 
are limitations to chronic monthly therapy. By exploring a treat and extend 
strategy once disease activity is under control, the investigators postulate that 
extending maintenance intervals can preserve the gains of initial monthly 
injections and reduce treatment burden.   
 
3.3 
OUTCOME MEASURES 
3.3.1 Primary Outcome Measure 
 
Mean change in ETDRS visual acuity at 24 months (week 92 – week 
107) from Day 0.  
 
3.3.2 Secondary Outcome Measures 
 Incidence and severity of adverse events (ocular and non-ocular). 
 Total number of intravitreal injections required during each year of the study 
period (week 52, week 104, and week 156). In a separate proof of concept 
analysis, the number of intravitreal injections in the TREX and GILA cohorts 
over the 36-month study period will be compared with that of the other two 
cohorts (p = 0.20) 
 Total number of office visits and imaging studies performed during  each 
 
year of the study period (week 52, week 104, and week 156). 
 
 Mean change in central foveal thickness per SDOCT from randomization to 
12  months (week 46 – week 57),randomization to 24 months (week 92 – week 
107), and randomization to 36 months (week 156). 
 
 Percentage of eyes gaining or losing 3 lines of vision or more and 1 line of 
vision 
 
or more at 6 months (week 22 – week 29),12 months (week 46 – week 57), 
18  


 
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months (week 70 – week 85),24 months (week 92 – week 107), and 36 
 
months (week 156) from Day 0. 
 
 Noninferiority comparison (margin of 9 letters) of mean change in ETDRS 
vision 
 
from Day 0 to 24 months (week 92 – week 107) between the three study 
groups.  
 
 The percentage of eyes which show progression of proliferative diabetic  
 
retinopathy requiring panretinal photocoagulation and/or pars plana 
vitrectomy  
 
over the 36-month study period. 
 
 The percentage of eyes in the TREX and GILA cohorts who are eligible to 
begin  
 
the extension phase after 4 treatment visits. 
 For TREX and GILA Cohorts, the time to achieve a “Secondary or Tertiary 
Baseline” retinal thickness. 
 Percentage of eyes in each cohort that have shown a two-step change 
(increase and decrease) in diabetic retinopathy at 24 months and 36 months 
from day 0. 
 
3.4 
SAFETY PLAN 
The safety assessments to be conducted for this study are listed in 
Section 5 and Appendix A. 
The safety and tolerability of intravitreal ranibizumab injections have been 
investigated in previous Phase I, I/II, III, and IIIb studies in AMD.  Potential 
safety issues associated with the route of administration or the pharmacology of 
ranibizumab in the study population include decreased BCVA, intraocular 
inflammation intraocular infection, transient and/or sustained elevation of 
intraocular pressure (IOP), cataract development or progression, retinal or 
intravitreal hemorrhage, macular edema, retinal break or detachment, and 
arterial thromboembolic events (ATEs).  Safety will be assessed by visual 
acuity, ophthalmic examinations including intraocular measurements, 
fluorescein angiograms, adverse events and vital signs. 
To minimize the risks of intraocular injections, all injections will be performed 
employing surgical sterile techniques as described in Appendix B.  Following 
each injection, subjects will have a retinal examination either by indirect 
ophthalmoscopy or checking subject’s ability to see (at investigator’s discretion) 
to ensure that there is a good perfusion of retinal vessels. 
Study drug administration will be held for subjects who experience certain 
ocular events or infection events. In the event any subject develops an adverse 
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intensity, serious consideration should be given to withdrawing the subject from 
the study. 
All adverse events will be reviewed by the PI on an ongoing basis. 
 
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 
150 eyes from approximately 3 sites in the United States will be enrolled. 
Eligible subjects who have provided informed consent will be screened for 
eligibility before the initiation of any study procedures. Screening evaluations 
may be performed at any time within the 14 days preceding Day 0. These 
subjects must have center involved diabetic macular edema, with evidence of 
activity seen on SD-OCT.  
 
 (See attached 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 > 18 years of age 
 Patient-related considerations 
 For sexually active women of childbearing potential, agreement 
to the use of an appropriate form of contraception (or abstinence) 
for the duration of the study  
 Although no birth control method is 100% effective, the following 
are  
considered effective means of contraception:  surgical 
sterilization, use of oral contraceptives, barrier contraception 
using either a condom or diaphragm with spermicidal gel, an 
intrauterine device, or contraceptive hormone implant or patch.  A 
patient’s primary care physician, obstetrician, or gynecologist 
should be consulted regarding an appropriate form of birth 
control.  


 
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 Ability and willingness to return for all scheduled visits and assessments  
 
Disease-related considerations 
 The presence of center-involving diabetic macular edema on clinical 
exam and SD-OCT 
 Best corrected visual acuity in the study eye, using ETDRS testing, 
between 20/25 and 20/320 (Snellen equivalent), inclusive.  
 Clear ocular media and adequate pupillary dilation to permit good quality 
fundus imaging.  
4.1.3 Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this 
study:  
 
General Exclusion Criteria 
 Pregnancy (positive urine 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. 
 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 
 
Ocular Exclusion Criteria 
Prior Ocular Treatment  
 History of active proliferative diabetic retinopathy in the study eye 
on clinical exam 
 History of vitrectomy surgery, submacular surgery, or other 
intraocular surgical intervention for diabetic macular edema in the 
study eye  
 Any previous intravitreal drug delivery (e.g., intravitreal 
corticosteroid injection, anti-VEGF drugs including ranibizumab, 
or device implantation) in the study eye within 90 days of the 
screening visit.  
 History of prior laser macular photocoagulation more than 90 days prior 
to screening will be eligible for study inclusion.  However, if the 
investigator does not feel that additional laser photocoagulation can be 
safely performed or would benefit the patient, then the eye in 
consideration will be excluded. 


 
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 Evidence of vitreomacular interface abnormality or epiretinal 
membranes which may be responsible for macular edema 
 
Concurrent Ocular Conditions  
 Any concurrent intraocular condition in the study eye (e.g., 
cataract or macular degeneration) that, in the opinion of the 
investigator, could either:  
Require medical or surgical intervention during the 24-month 
study period to prevent or treat visual loss that might result from 
that condition; or if allowed to progress untreated, could likely 
contribute to loss of at least 2 Snellen equivalent lines of BCVA 
over the 24-month study period.  
 Active intraocular inflammation (grade trace or above) in the 
study eye  
 Current vitreous hemorrhage in the study eye  
 History of rhegmatogenous retinal detachment or macular hole 
(Stage 3 or 4) in the study eye  
 Active infectious conjunctivitis, keratitis, scleritis, or 
endophthalmitis in either eye  
 Aphakia in the study eye  
 Intraocular surgery (including cataract surgery) in the study eye 
within 3 months preceding Day 0  
 Uncontrolled glaucoma in the study eye (defined as IOP ≥ 30 
mmHg despite treatment with anti-glaucoma medication)  
 History of glaucoma-filtering surgery in the study eye  
 History of corneal transplant in the study eye  
 History of pars plana vitrectomy 
 
Concurrent Systemic Conditions  
 Any history of use of systemic anti-VEGF agents 
 Uncontrolled blood pressure (defined as systolic > 180 mmHg 
and/or diastolic > 110 mmHg while patient is sitting)  
If a patient’s initial reading exceeds these values, a second 
reading may be taken 30 or more minutes later.  If the 
patient’s blood pressure needs to be controlled by 
antihypertensive medication, the patient can become eligible 
if medication is taken continuously for at least 30 days prior to 
Day 0.  
 Atrial fibrillation not managed by patient’s primary care physician 
or cardiologist within 3 months of screening visit  
 Women of childbearing potential not using adequate 
contraception (as defined in the inclusion criteria).  
A woman is considered not to be of childbearing potential 
if she is postmenopausal, defined by amenorrhea for at 


 
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least 1 year in a woman > 45 years old; or has undergone 
hysterectomy and/or bilateral oophorectomy.    
 History of stroke within the last 3 months of screening visit  
 History of other disease, metabolic dysfunction, physical 
examination finding, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that 
contraindicates the use an investigational drug or that might 
affect interpretation of the results of the study or renders the 
patient at high risk for treatment complications  
 Current treatment for active systemic infection  
 Active malignancy  
 History of allergy to fluorescein, not amenable to treatment  
 Inability to obtain fundus photographs or fluorescein angiograms 
of sufficient quality to be analyzed and graded by the reading 
center   
 Inability to comply with study or follow-up procedures  
 Previous participation in any studies of investigational drugs 
within 1 month preceding Day 0 (excluding vitamins and 
minerals)  
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
All eyes which satisfy all inclusion/exclusion criteria will be randomized 1:2:2 
into the Monthly:TREX:GILA Cohorts. Screening evaluations may be performed 
at any time within the 14 days preceding Day 0.  Randomization will occur at 
Day 0.  
 
Baseline Measurement For the TREX and GILA cohorts: 
Eyes which have a central foveal thickness  325 m at week 12, a 
“Primary Baseline” retinal thickness will be defined as the thinnest 
central foveal thickness on SD-OCT over the first four visits of monthly 
treatment.  Eyes which have a central foveal thickness > 325 m at 
week 12 will continue to receive monthly intravitreal injections of 0.3 mg 
ranibizumab and guided laser photocoagulation every 3 months if 
leakage is present on fluorescein angiography until the central foveal 
thickness is  325 m, at which point their “Primary Baseline” retinal 
thickness will be established.   
If at any point in the study period, the study eye has improved more 
than 20% from the primary baseline thickness for three consecutive 
visits and there is less than 50 microns of variability in central foveal 
thickness between these visits, then a “Secondary Baseline” retinal 
thickness will be established.  This “Secondary Baseline” retinal 
thickness will then be used for treatment interval determinations from 
that point forward. If the study eye has improved more than 20% from 
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is less than 50 microns of variability in central foveal thickness between 
these visits, then a “Tertiary Baseline” retinal thickness will be 
established.  This “Tertiary Baseline” retinal thickness will then be used 
for treatment interval determinations from that point forward.   
 
Treatment Groups: 
Monthly Cohort (30 eyes) – Study eyes will receive intravitreal 
injections of 0.3 mg ranibizumab every 28 days (+/- 7) for 36 months, 
relative to the date of the first injection (Day 0), unless indicated below.   
Starting at week 104, study eyes will have the opportunity to undergo 
treatment on a pro re nata (PRN) basis.  Thus, eyes who have a central 
subfield thickness (CST) ≤ 325 microns at the week 104 visit, will not be 
given treatment at week 104.  Eyes will continue to be seen every 4 
weeks and will be given an intravitreal injection of ranibizumab 0.3 mg 
only if the CST is > 325 microns.  Eyes will also receive treatment if 
there is a > 5 letter loss due to DME (compared to the vision at week 
104), regardless of thickness on OCT.   
 
Subjects will be evaluated for focal laser treatment at week 116, week 
128, week 140, and week 152.  If the subject has received ≥ 2 
intravitreal injections of ranibizumab within the prior 90 day period, then 
fluorescein angiography will be performed and focal laser treatment will 
be applied to any leaking microaneurysms.  If the patient does not meet 
this criteria for focal laser treatment, then fluorescein angiography and 
focal laser treatment will be deferred and reassessed at the subsequent 
laser evaluation visit. Focal laser treatment and focal laser re-treatment 
will be administered no more than once every 90 days. 
 
Focal laser therapy will be applied to all leaking microaneurysms on 
fluorescein angiography.  Focal laser therapy will not be applied if 
significant macular ischemia is present involving the foveal avascular 
zone (once this has been determined additional fluorescein angiography 
and focal laser treatment planning should not be performed as the 
subject will no longer be eligible for focal laser treatment).  Focal laser 
will also not be applied if treatment is considered too close to the foveal 
avascular zone or to macular edema not related to DME (cystoid 
macular edema, etc.).  If no microaneurysms are present on fluorescein 
angiography, then focal laser therapy should be deferred and 
reassessed with repeat fluorescein angiography at the first visit that 
occurs after 90 days. 
 


 
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TREX Cohort (60 eyes) – Monthly intravitreal injections of 0.3 mg 
ranibizumab for four visits. At the fourth visit (Week 12), if the central 
foveal thickness is  325 m then the eye will receive 0.3 mg 
ranibizumab and begin the extension phase of the study.  For all 
subsequent visits in the extension phase, appropriate changes to the 
treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, 
reduce) will be made based on pre-specified SD-OCT criteria.  
Treatment is rendered at every visit, no earlier than 7 days before the 
target date and no later than 7 days after the target date, but the time 
between visits is individualized based on each subject’s response to 
treatment.  If the central foveal thickness is > 325 m at week 12, then 
the patient will continue to receive monthly intravitreal injections of 0.3 
mg ranbizumab until the central foveal thickness is  325 m.  Once the 
central foveal thickness is  325 m, then the study eye will begin the 
extension phase of the study. 
Starting at week 104, study eyes will have the opportunity to undergo 
treatment on a pro re nata (PRN) basis.  Thus, eyes who have a central 
subfield thickness (CST) ≤ 325 microns at the week 104 visit, will not be 
given treatment at week 104.  Starting at week 104, eyes will be seen 
every 4 weeks and will be given an intravitreal injection of ranibizumab 
0.3 mg only if the CST is > 325 microns.  Eyes will also receive 
treatment if there is a > 5 letter loss due to DME (compared to the vision 
at week 104), regardless of thickness on OCT.   
 
Subjects will be evaluated for focal laser treatment at week 116, week 
128, week 140, and week 152.  If the subject has received ≥ 2 
intravitreal injections of ranibizumab within the prior 90 day period, then 
fluorescein angiography will be performed and focal laser treatment will 
be applied to any leaking microaneurysms.  If the patient does not meet 
this criteria for focal laser treatment, then fluorescein angiography and 
focal laser treatment will be deferred and reassessed at the subsequent 
laser evaluation visit. Focal laser treatment and focal laser re-treatment 
will be administered no more than once every 90 days. 
 
Focal laser therapy will be applied to all leaking microaneurysms on 
fluorescein angiography.  Focal laser therapy will not be applied if 
significant macular ischemia is present involving the foveal avascular 
zone (once this has been determined additional fluorescein angiography 
and focal laser treatment planning should not be performed as the 
subject will no longer be eligible for focal laser treatment).  Focal laser 
will also not be applied if treatment is considered too close to the foveal 
avascular zone or to macular edema not related to DME (cystoid 


 
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macular edema, etc.).  If no microaneurysms are present on fluorescein 
angiography, then focal laser therapy should be deferred and 
reassessed with repeat fluorescein angiography at the first visit that 
occurs after 90 days. 
 
GILA Cohort (60 eyes) – Monthly intravitreal injections of 0.3 mg 
ranibizumab for four visits combined with GuIded LAser (GILA) 
photocoagulation to all microaneurysms in the area of DME at the 
second visit (Week 4). Fluorescein angiography is to be repeated 
approximately every 3 months (the first visit that occurs ≥ 90 days from 
the preceding fluorescein angiography visit). Guided laser will be 
repeated at those visits if leakage is present from microaneurysms.  If 
the central foveal thickness is  325 m at the fourth visit (Week 12), 
eyes will receive 0.3 mg ranibizumab and the extension phase will 
begin.  For all subsequent visits in the extension phase, appropriate 
changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, 
maintain, reduce) will be made based on pre-specified SD-OCT criteria. 
Treatment is rendered at every visit, no earlier than 7 days before the 
target date and no later than 7 days after the target date, but the time 
between visits is individualized based on each subject’s response to 
treatment.  If the central foveal thickness is > 325 m at week 12, then 
the patient will continue to receive monthly intravitreal injections of 0.3 
mg ranbizumab and possible guided laser every 3 months until the 
central foveal thickness is  325 m.  Once the central foveal thickness 
is  325 m, then the study eye will begin the extension phase of the 
study. 
Starting at week 104, study eyes will have the opportunity to undergo 
treatment on a pro re nata (PRN) basis.  Thus, eyes who have a central 
subfield thickness (CST) ≤ 325 microns at the week 104 visit, will not be 
given treatment at week 104.  Starting at week 104, eyes will be seen 
every 4 weeks and will be given an intravitreal injection of ranibizumab 
0.3 mg only if the CST is > 325 microns.  Eyes will also receive 
treatment if there is a > 5 letter loss due to DME (compared to the vision 
at week 104), regardless of thickness on OCT.   
 
After week 104, subjects will be evaluated for focal laser treatment in 
the same manner as the Monthly and TREX Cohorts.  Subjects will be 
evaluated for focal laser treatment at week 116, week 128, week 140, 
and week 152.  If the subject has received ≥ 2 intravitreal injections of 
ranibizumab within the prior 90 day period, then fluorescein angiography 
will be performed and focal laser treatment will be applied to any leaking 
microaneurysms.  If the patient does not meet this criteria for focal laser 
treatment, then fluorescein angiography and focal laser treatment will be 


 
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deferred and reassessed at the subsequent laser evaluation visit. Focal 
laser treatment and focal laser re-treatment will be administered no 
more than once every 90 days. 
 
Focal laser therapy will be applied to all leaking microaneurysms on 
fluorescein angiography.  Focal laser therapy will not be applied if 
significant macular ischemia is present involving the foveal avascular 
zone (once this has been determined additional fluorescein angiography 
and focal laser treatment planning should not be performed as the 
subject will no longer be eligible for focal laser treatment).  Focal laser 
will also not be applied if treatment is considered too close to the foveal 
avascular zone or to macular edema not related to DME (cystoid 
macular edema, etc.).  If no microaneurysms are present on fluorescein 
angiography, then focal laser therapy should be deferred and 
reassessed with repeat fluorescein angiography at the first visit that 
occurs after 90 days. 
 
 End-Point Visits 
Subjects will continue to receive study treatments according to the above 
treatment protocol until week 104.  A “Hard End-Point Visit” will occur at 
week 52, week 104, and week 156.  A “Biologic End-Point Visit” will occur 4 
weeks after the previous injection near the 12-month time point (week 46 – 
week 57),24-month time point (week 92 – week 107), and 36-month time 
point (week 156).  Only best corrected visual acuity and SD-OCT 
measurements will be recorded at these endpoint visits.  No study treatment 
will be given at these end-point visits, unless the patient has a regular study 
treatment visit at these time points. 
 
Study eyes which have not met criteria allowing them to extend to at least 6 
weeks for two consecutive visits by the week 52 hard endpoint visit will 
receive a series of three intravitreal injections of ranibizumab 0.3 mg every 4 
weeks regardless of OCT measurement, beginning at week 52 if treatment 
is indicated at that time or the first treatment visit thereafter. The study eye 
will resume treatment interval determinations based on the pre-specified 
criteria at the time of the third monthly intravitreal injection. 
 
 
Fellow eyes not enrolled into a study group and that have DME during the 
 
course of the study may be treated with standard of care macular laser 
 
photocoagulation and/or intravitreal injections of 0.3 mg of ranibizumab at 
 
the Investigator’s discretion.  Ranibizumab will be provided by Genetech for 
 
treatment of DME in the fellow eye. 
 


 
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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.  This results in the 
delivery of a 0.3 mg dose of ranibizumab.  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 
Patient will be to receive intravitreal injections of 0.3 mg of ranibizumab. 
 
b. Administration 
 
*  *See Appendix B for detailed preparation and administration of 
ranibizumab injection. 
 
 
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 
Subjects may continue to receive all medications and standard 
treatments administered for their conditions at the discretion of their 
treating physician except non-ranibizumab intraocular therapies for 
DME, including corticosteroids and other anti-VEGF agents.   
4.5 
STUDY ASSESSMENTS 
4.5.1 Assessments during the Treatment Period 
See the table of events for the exact assessments at each visit. 
Vital Signs (All Study Visits)  


 
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Vital signs will include measurements of pulse and systolic and diastolic blood 
pressure while the patient is in a seated position.  Vital signs should be taken 
before injection of study drug.   
Ocular Assessments (All Study Visits) 
 Best Corrected Visual Acuity Visual function of the study eye and the 
fellow eye will be assessed using the ETDRS protocol (The Early 
Treatment Diabetic Retinopathy Study Group, 1985) at 4 meters.  After 
week 104, a new manifest refraction will be performed at week 116, 
week 128, week 140, and week 156.  The pre-existing refraction will be 
used to test visual acuity at 4 meters in the intervening visits between 
weeks 104 and week 156. 
 IOP measurement- (perform prior to dilating eyes and post intravitreal 
injection; the method used for a patient must remain consistent 
throughout the study). IOP may be measured either by TonoPen or 
applanation tonometry, but the method of measurement must remain 
consistent for each patient throughout the study.  
 Slit lamp examination- Patient’s anterior eye structure and ocular 
adnexa will be examined at each study visit using a slit lamp by the 
investigator. 
 Indirect Ophthalmoscopy- The patient’s posterior pole and peripheral retina will 
be examined by indirect ophthalmoscopy at each study visit pre dose (bilateral) 
by the investigator  
 
Ocular Imaging   
Fundus Photography and Fluorescein Angiography (FA) 
 
The anatomical state of the retinal vasculature of the study eye will be 
evaluated by funduscopic examination, fundus photography and FA.   Fundus 
photography and Fluorescein angiography will be done in the Monthly and 
TREX Cohorts at baseline (screening visit) and again at week 12, month 
12,month 24, and month 36.  Fundus photography and fluorescein angiography 
will be done in the GILA Cohort at baseline (screening visit), and again at week 
4, and then approximately every three months (first visit that occurs > 90 days 
from previous fluorescein angiogram). See Appendix A.  Fluorescein 
angiography will be used to guide focal laser treatment for all treatment cohorts 
at week 116, week 128, week 140, and week 152 if laser treatment criteria has 
been met.   
 
Optical Coherence Tomography (All Study Visits) – 
 
Ocular morphology will be evaluated using the Heidelberg Spectralis Domain 
(SD) OCT on the study eye. All SD-OCT images will be captured using the 


 
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most current software. All SD-OCTs will be electronically archived at the site as 
part of the source documentation.  
Microperimetry –  
 
Microperimetry will be performed at the locations where a microperimeter is 
available on all study eyes in the TREX and GILA cohorts at screening, week 
24, week 52 and week 104, or the closest visit to these time points. 
 
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 reason: if it is in 
the best interest of the subject, intercurrent illness, adverse events, or 
worsening condition.  Palmetto Retina Center, LLC or John F. Payne, 
MD 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 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 


 
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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 
Palmetto Retina Center, LLC or Genentech may terminate this study 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 
The analysis of complete data (36-month treatment period) for the study 
will be performed when all patients have either completed the visit at 
month 36 or discontinued early from the study, all data collected from 
the study are in the database, and the database is locked.  
Interim analysis of data from the 12-month period will be performed 
when all patients have either completed the visit at month 12 or 
discontinued early from the study.  Treatment assignment will be 
unmasked to the personnel performing the analysis when all data 
collected through month 12 are in the database and the data have been 
cleaned and verified. The Peto group sequential procedure (Z +/- 3.0 at 
all interim analyses) will be used to control for the possibility of type I 
error arising from the 12 month interim analysis.  
For the primary objective, power calculations for different margins were 
undertaken.  Familywise alpha of 0.05 was divided equally among three 
TOST (two one sided test) procedures (alpha=0.0167): (1) comparing 
TREX vs. GILA in the 60 patients enrolled with bilateral disease, (2) 
TREX vs. control (total n=90, controls n=30), and (3) GILA vs. control 
(total n=90, controls n=30).  A standard deviation of 11 letters was used 
for the power calculations and based from the RISE/RIDE data for 
subjects with DME. The power calculations suggests that the minimum 
boundary of equivalence for TREX vs. GILA that we can demonstrate is 
+/- 7 letters (less than two lines of vision) and +/- 9 letters (less than two 
lines of vision) for TREX and GILA vs. controls.  Paired sample t-test will 
be used to compare TREX vs. GILA and two sample t-test will be used 
to compare the two groups vs. controls.  
Because of the potential for confounding of the effect when comparing 
the control group (monthly cohort) to the TREX and GILA groups, we 
will use linear regression modeling with change in ETDRS as outcome 


 
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and cohort as main effect controlling for potential confounders (e.g., 
age, race, sex).  
Adverse events, number of injections, and number of office visits will be 
approached statistically with descriptive analyses with point estimates 
and confidence limits provided.  Exploratory linear, logistic, and time-to-
event models will be used to analyze the other secondary outcomes. 
 
4.8.2 Safety Analyses 
Any adverse events, laboratory assessments, physical examinations, 
vital signs, ocular examinations and measurements from all 150 eyes 
will be utilized to summarize safety data for this study. 
 Incidence and severity of adverse events (ocular and non-ocular). 
 
4.8.3 Efficacy Analyses 
Primary Endpoint 
 Mean change in ETDRS visual acuity at 24 months (week 92 – week 107) from 
Day 0. 
 
Secondary Endpoints 
 Incidence and severity of adverse events (ocular and non-ocular). 
 Total number of intravitreal injections required during each year of the study 
period. In a separate proof of concept analysis, the number of intravitreal 
injections in the TREX and GILA cohorts over the 36-month study period will be 
compared with that of the other two cohorts (p = 0.20) 
 Total number of office visits and imaging studies performed during each year of 
the study period (week 52, week 104, and week 156). 
 
 Mean change in central foveal thickness per SDOCT from randomization to 12 
months (week 46 – week 57),randomization to 24-months (week 92 – week 
107), and randomization to 36 months (week 156).. 
 
 Percentage of eyes gaining or losing 3 lines of vision or more and 1 line of 
vision or more at 6 months (week 22 – week 29),12 months (week 46 – week 
57),18 months (week 70 – week 85),24 months (week 92 – week 107), and 36 
months (week 156) from Day 0. 
 
 Noninferiority comparison (margin of 9 letters) of mean change in ETDRS 
vision from Day 0 to 24 months (week 92 – week 107) between the three study 
groups.   
 


 
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 The percentage of eyes which show progression of proliferative diabetic 
retinopathy requiring panretinal photocoagulation and/or pars plana vitrectomy 
over the 36-month study period. 
 
 The percentage of eyes in the TREX and GILA cohorts who are eligible to 
begin the extension phase after 4 treatment visits. 
 For TREX and GILA Cohorts, the time to achieve a “Secondary or Tertiary 
Baseline” retinal thickness. 
 Percentage of eyes in each cohort that have shown a two-step change 
(increase and decrease) in diabetic retinopathy at 24 months and 36 months 
from day 0. 
 
 
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 
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 
5. 
SAFETY REPORTING OF ADVERSE EVENTS 
 
 
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 Lucentis, 
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. 


 
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 
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. 
 
 
Pre-existing 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. 
 
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 
following  
the last 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. 


 
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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 Lucentis (see following guidance), and 
actions taken. 
 
 
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 the Lucentis, 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 Lucentis; and/or the AE abates or 
resolves  
upon discontinuation of the Lucentis or dose reduction and, if applicable, 
reappears  
upon re-challenge. 
 
 
No 
 
 
Evidence exists that the AE has an etiology other than the Lucentis (e.g., pre-
existing  
medical condition, underlying disease, intercurrent illness, or 
concomitant  medication); and/or the AE has no plausible temporal relationship to 
Lucentis  
administration (e.g., cancer diagnosed 2 days after first dose of 
Lucentis). 
 
 
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 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING 
ADVERSE EVENTS 
5.4.1 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?” 


 
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 
“Have you had any new or changed health problems since you were last 
 
here?”  
 
 
5.4.2 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  
unknown and cannot be ascertained at the time of 
reporting, report “Unexplained  
Death”. 
 
c. 
Pre-existing Medical Conditions 
 
A pre-existing medical condition is one that is present at the start of the study. 
Such  conditions should be reported as medical and surgical history. A pre-existing 
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 pre-existing  
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 


 
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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  90 days after the last dose of Lucentis, 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 Lucentis should be reported as an SAE. 
 
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 
Lucentis 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 


 
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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:  
 
Endophthalmitis  
 
Intraocular inflammation (including vitritis and uveitis)  
 
Cataract (Traumatic)  
 
Increased IOP 
 
ATEs including stroke 
 
Retinal Pigment 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: 
 
(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 Lucentis 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 Lucentis 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 
Lucentis  
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. 


 
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5.4.3 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 
 
5.4.4 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) 
 
 
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  
 
 
5.4.5 Additional Reporting Requirements for IND Holders 
 


 
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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 Lucentis. An unexpected adverse event is one that is not 
already described  in the Lucentis 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 Lucentis. An unexpected 
adverse event is  
one that is not already described in the Lucentis investigator 
brochure. 
 
 
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 
 


 
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For questions related to safety reporting, please contact Genentech Drug 
Safety: 
 
Tel: (888) 835-2555 
 
Fax: (650) 225-4682 or (650) 225-5288 
 
 
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  Clinical Operations contact for the study: 
 
 
E-mail: lucentisgsr_coa-d@gene.com 
 
Fax: 866-728-4622 
 
 


 
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5.4.6 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 
Palmetto Retina Center 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 
Palmetto Retina Center, 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 Palmetto Retina Center 
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) 
 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) 


 
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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. 
 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 Palmetto Retina Center 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 


 
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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 
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 Palmetto Retina Center (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.  
 


 
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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. 
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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7.0 
REFERENCES 
The ACCORD Study Group and ACCORD Eye Study Group. Effects of medical 
therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-
44. 
Centers for Disease Control and Prevention. National diabetes fact sheet: general 
information and national estimates on diabetes in the United States, 2007. 
http://www.cdc.gov/diabetes/pubs/factsheet07.htm.  Accessed June 6, 2010. 
 
 
Diabetes Control and Complications Trial Research Group. The effect of intensive 
 
treatment of diabetes on the development and progression of long-term complications 
 
in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986. 
 
 
Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, et 
 
al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or 
 
triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 
 
2010;117:1064-1077. 
 
 
 
Diabetic Retinopathy Study Research Group. Photocoagulation treatment of 
 
proliferative diabetic retinopathy: the second report of Diabetic Retinopathy Study 
 
findings. Am J Ophthalmol. 1978;85:82-106. 
 
 
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. 
 
 
Early Treatment of Diabetic Retinopathy Study Group. Photocoagulation for Diabetic 
 
Macular Edema. Early Treatment of Diabetic Retinopathy report number 1. Arch 
 
Ophthalmol. 1985;103:1796-1806. 
 
 
Fong DS, Aiello L, Gardner TW, et al. Diabetic Retinopathy. Diabetes Care. 
 
2003;26:226-9. 
 
 
 
Ho AC, Scott IU, Kim SJ, et al. Anti-Vascular Endothelial Growth Factor 
 
Pharmacotherapy for Diabetic Macular Edema. Ophthalmology. 2012;119:2179-2188. 
 
 
International Diabetes Federation. Fact Sheet: Diabetes and Eye Disease. Available 
 
at: http://www.idf.org/fact-sheets/diabetes-eye-disease. Accessed October 16, 2012. 
 
 
Kernt M, Cheuteu RE, Cserhati S. Pain and accuracy of focal laser treatment for 
 
diabetic macular edema using a retinal navigated laser (Navilas®). Clin Ophthalmol. 
 
2012;6:289-296. 
 
 
Kozak I, Oster SF, Cortes MA, et al. Clinical evaluation and treatment accuracy in 
 
diabetic macular edema using navigated laser photocoagulator NAVILAS. 
 
Ophthalmology. 2011;118:1119-1124. 


 
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Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory 
 
diabetic macular edema. Ophthalmology. 2002;109:920-927. 
 
 
Mitchell P, Bandello F, Schmidt-Erfurth U, et al, RESTORE Study Group. The 
 
RESTORE Study: ranibizumab monotherapy or combined with laser versus laser 
 
monotherapy for diabetic macular edema. Ophthlamology. 2011;118:615-625. 
 
 
 
Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M. 
 
Corticosteroids Inhibit the Expression of the Vascular Endothelial Growth Factor Gene 
 
in Vascular Smooth Muscle Cells. Eur J Pharmacol. 1998;341:309-15. 
 
 
Nguyen QD, Brown DM, Marcus DM, et al, RISE and RIDE Research Group. 
 
Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: 
 
RISE and RIDE. Ophthalmology. 2012;119:789-801. 
 
 
 
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. Arch Ophthalmol. 2012 (Epub 
 
ahead of print). 
 
 
Sultan MB, Zhou D, Loftus J, et al; Macugen 1013 Study Group. A phase 2/3, 
 
multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the 
 
treatment of diabetic macular edema. Ophthalmology. 2011;118:1107-1118. 
 
 
 
UK Prospective Diabetes Study Group. Tight blood pressure control and risk of 
 
macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ  
 
1998;317:703-713. 
 
 
UK Prospective Diabetes Study Group: Intensive blood-glucose control with 
 
sulphonylureas or insulin compared with conventional treatment and risk of 
 
complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. 
 
 
Vinores SA, Derevjanik NL, Ozaki H, Okamoto N, Campochiaro PA. Cellular 
 
mechanisms of blood-retinal barrier dysfunction in macular edema. Doc Ophthalmol. 
 
1999;97:217-228. 
 
 
Yau JWY, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors for 
 
diabetic retinopathy. Diabetes Care. 2012;35:556-64. 
 
 


 
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APPENDIX A 
Study Flowchart  
 
The study flowchart will be sent as a separate document. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX B 
Pre-Administration,, Administration, and Post-Administration 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).  
Clinic staff will observe aseptic technique 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 technician assembles the supplies and prepares a sterile field. Supplies include 
10% povidone iodine swabs, sterile surgical gloves, 4x4 sterile pads, pack of sterile 
cotton-tipped applicators, eyelid speculum, 0.5% proparacaine hydrochloride, 1 or 2% 
lidocaine( without epinephrine) for subconjunctival injection (at investigator’s 
discretion), ophthalmic antimicrobial solution (e.g. trimethoprim-polymyxin B 
ophthalmic solution, ofloxacin ophthalmic solution, ophthalmic gatifloxacin solution, 
ophthalmic moxifloxacin solution), and injection supplies 
 
Pre-Administration 
 Instill 2 drops of 0.5% proparacaine hydrochloride into the study eye, followed by 
2 drops of a broad-spectrum antimicrobial solution (e.g. trimethoprim-polymyxin B 
ophthalmic solution, ofloxacin ophthalmic solution, ophthalmic gatifloxacin 
solution, ophthalmic moxifloxacin solution). 
 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, place sterile ophthalmic drape to isolate the field, 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 or 2% 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. 


 
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 Instruct subject to direct gaze away from syringe prior to ranibizumab injection. 
Administration of Intravitreal Injection 
 Using aseptic technique, all of the ranibizumab vial contents are withdrawn through a 5 
µm, 19g filter needle attached to a 1cc tuberculin syringe. 
 The filter needle should be discarded after withdrawal of the vial contents and should not 
be used for intravitreal injection. 
 Replace the filter needle with a sterile 30g, ½” needle for the injection 
 Expel the contents of the syringe until the plunger tip is aligned with the line that marks 
0.05mL. 
 Administer intravitreal injection through the pars plana either inferiorly or superiorly from a 
temporal approach, 3.5-4 mm posterior to the corneal scleral limbus. 
 As the needle is withdrawn, a sterile cotton-tipped applicator is rolled over the injection 
site. 
Post-Administration 
 Instill broad spectrum antibiotic at the injection site. 
 Thoroughly rinse the treated eye with sterile ophthalmic solution. 
 Confirm adequate retinal perfusion by either indirect ophthalmoscopy or evaluating 
subject’s ability to see from the study eye (investigator’s discretion). 
 Measure intraocular pressure (IOP) 30 minutes (± 15 minutes) after the injection. Subject 
will continue to be monitored until IOP is ≤30 mmHg. 
 Patients should be instructed to report any symptoms suggestive of endophthalmitis 
without delay. 
 
Should a site’s injection procedure differ from above they may submit to sponsor for 
approval.


 
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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.  The responsible principal investigator should write this section. 
 
*  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. 
 


 
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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, Palmetto Retina Center 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. 
 
 
 
 
Or 
Based on review of available data, the Palmetto Retina Center 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 Palmetto Retina Center 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 Palmetto Retina Center 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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