Clinical trial NCT01552408
Conditions: Diabetic Macular Edema
Keywords: Non Proliferative Diabetic Retinopathy Diabetic Retinopathy Macular Edema Background Diabetic Retinopathy Pre Proliferative Diabetic Retinopathy
Sponsor: David M. Brown, M.D.
Start date: 2012-03-01; Completion date: 2017-05-18
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a Phase I/II, multicenter, randomized, study of the efficacy and safety of ranibizumab injection monotherapy verses a duel therapy of 0.3mg ranibizumab combined with ultra wide, 200° field angiography guided pan retinal photocoagulation in patients with CSME-CI secondary to diabetes mellitus (Type 1 or 2).

Detailed description:
Approximately 40 eyes will be randomized at 3 investigational centers in the United States. This study consists of a screening period of up to 14 days (Days -14 to -1), and a 36-month treatment period (Day 0 to Month 36). Subjects who provide consent will enter the screening period to determine eligibility. As part of the screening process, the examining investigator will evaluate the macular foveal avascular zone fluorescein images to determine subjects' eligibility. Eligible subjects will be randomized in a 1:1 ratio so that approximately 20 eyes will receive 0.3 mg ranibizumab monotherapy, and approximately 20 eyes will receive 0.3 mg ranibizumab combined with Ultra wide 200° field angiogram guided targeted pan retinal photocoagulation (PRP). Subjects must meet VA and retinal thickness eligibility requirements during the screening period. The subject can have both eyes in the study. If both eyes are eligible, one eye will be randomized, to cohort 1 while the other eye will be randomized to the cohort 2. A subject with both eyes in the trial will have each eye in a separate cohort.

Arms: arm 1: Cohort 1: Subjects will receive 4 IVT of 0.3 mg ranibizumab every 28 days (+/- 7 days), then will be seen monthly (+/- 7 days) \& will receive IVT of 0.3 mg ranibizumab on a pro re nata (PRN) schedule per retreatment criteria. arm 2: Cohort 2: Subjects will receive 4 it of 0.3 mg ranibizumab every 28 days (+/- 7 days), then will then be seen monthly (+/- 7 days) \& receive IVT of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at Day 7 they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide field angiography. Ultra wide field angiography will be performed every 3 months to indicate areas of peripheral ischemia, which will be selectively be treated with PRP at Month 6, Month 18, and Month 25, preserving areas of more perfused retina.
Interventions: intervention 1: 0.3 mg ranibizumab intervention 2: Targeted Pan Retinal Photocoagulation
Intervention descriptions: intervention 1: Cohort 1: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. intervention 2: Cohort 2: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan retinal photocoagulation (PRP) based on ultra wide 200º field angiography. After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.

Protocol documents:
Prot_SAP_000.pdf: 
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PROTOCOL 
Study Title: 
A Phase 1/11, 1 :1 Randomized, Multicenter Study for 
Diabetic Macular Edema Using 0.3mg Ranibizumab 
Combined with Ultra Wide 200° Field Angiography 
Guided Pan Retinal Photocoagulation Monthly for 4 
Months (Loading Dose), Then as Needed vs. 0.3 mg 
Ranibizumab 4 Months (Loading Dose) Monotherapy, 
Then as Needed (DME-AntiVEgf) DAVE 
Study drug: 
Recombinant Humanized Anti-VEGF 
Monoclonal Antibody Fragment (rhuFab V2 
[ranibizumab]) 
Sponsor: 
Retina Consultants of Houston 
6560 Fannin, Ste. 750 
Houston, Texas 77030 
IND: 
113691/ML27954 
Investigator: 
David M Brown, MD, FACS 
Sub-Investigators: 
Matthew Benz, MD 
Eric Chen, MD 
Richard H. Fish, MD 
Rosa Y. Kim, MD 
James C. Major, MD, PhD 
Amy C. Schefler, MD 
Sushma K. Vance, MD 
Tien P. Wong, MD 
Charles C. Wykoff, MD, PhD 
Date Final: 
10 JUNE 2014 
Amendment: 
7 


4. 
MATERIALS AND METHODS 
4.1 
Subjects 
22 
4.1.1 
Subject Selection 
22 
4.1.2 Inclusion Criteria 
22 
4.1.3 
Exclusion Criteria 
23 
4.2 
Method of Treatment Assignment 
25 
4.3 
Study Treatment 
26 
4.3.1 
Formulation 
26 
4.3.2 
Dosage, Administration, and Storage 
26 
4.4 
Concomitant and Excluded Therapies 
27 
4.5 
Study  Assessments 
27 
4.5.1 Assessments During the Treatment Period 
27 
4.5.2 
Early Termination  Assessments 
28 
4.6 
Subject Discontinuation 
28 
4.7 
Study Discontinuation 
29 
4.8 
Statistical Methods 
29 
4.8.1 Analysis of the Conduct of Study 
29 
4.8.2 
PK/PD Analyses 
30 
4.8.3 
Genetic Sample Collection and Analysis 
30 
4.8.4 
Safety Analyses 
30 
4.8.5 
Efficacy  Analyses 
31 
4.8.6 
Missing Data 
31 
4.8.7 
Interim Analyses 
31 
4.9 
Data Quality Assurance 
32 
5. 
ASSESSMENT OF SAFETY 
5.1 
Adverse Events 
32 
5.2 
Serious Adverse Events 
32 
5.3 
Methods  and Timing for Assessing  and Recording  Safety Events 
33 
5.4 
Evaluations 
35 
5.5 
Vital Signs 
35 
5.6 
Procedures for Eliciting, Recording, and Reporting Adverse Events 
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1. BACKGROUND 
1.1 Disease Overview 
Diabetic retinopathy is the leading cause of legal blindness in Americans aged 55- 
74, accounting for 8% of all legal blindness and 12% of the newly blind (Llein and 
Klein, 1995). Diabetic retinopathy is a common complication of Type 1 and Type 2 
diabetes, as well as for women with gestational diabetes, affecting more than 2.5% 
of the U.S. population, or more than 5.3 million Americans aged 18 or older 
(Friedman, et al., 2007). 
 
Age and race appear to play a role in the prevalence of diabetic retinopathy 
(Friedman, et al., 2007). Caucasians are the most commonly affected in the age 
group less than 40, as are Hispanics in the older than 40 population. The longer the 
duration of diabetes, the greater the risk there is of developing diabetic retinopathy. 
 
Three forms of retinopathy are commonly recognized in association with all forms of 
diabetes mellitus: 1) non-proliferative diabetic retinopathy (NPDR}, 2) proliferative 
diabetic retinopathy (PDR), and 3) diabetic macular edema (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, 1979). 
 
DME, the third form of diabetic retinopathy, is characterized by swelling of the 
central part of the retina that mediates high-resolution vision. DME frequently 
coexists with, and is superimposed upon NPDR or PDR. When the area of swelling 


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1.2 Treatment of Diabetic Macular Edema 
The current standard of care for DME is suboptimal. 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 (BCVA) 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 
often causes symptomatic Paracentral scotomas, which can become 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. 
 
1.2.1   Glucose Control 
Although glucose control does not have a direct treatment effect on macular edema, it 
plays a role in the management of diabetic retinopathy as a primary and secondary 
prevention strategy. In the time frame of 3 or more years, improving blood pressure 
slows progression of retinopathy (DCCT Research Group, 1993; UKPDS Research 
Group, 1998a, 1998b). The cumulative incidence and progression of retinopathy, 
defined as a change of three or more steps on fundus photography (FP) sustained over 
a 6-month period, was similar in the two treatment groups (conventional and intensive 
glucose control) until approximately 3 years. By 5 years of follow-up, there was a 
significant reduction in the risk of sustained progression of retinopathy by 78% in the 
intensive therapy group compared with the conventional therapy group in the primary 
prevention cohort. In the secondary intervention cohort, the progression of retinopathy 
In the secondary intervention cohort, the progression of retinopathy was reduced by 
54% in the intensive therapy group during the entire study period compared with those 
assigned to the conventional therapy group, while the need for laser treatment was 
reduced by 56%. This suggests that glycemic control is not necessarily efficacious in 
reducing the progression of retinopathy. There was a reduction in the incidence and 
progression of retinopathy for those receiving intensive treatment earlier in the course 


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likely to lose 15 or more letters on the ETDRS visual chart at 3 years than those who were 
not (12% vs. 25%). For the CSME-CI subgroup of CSME, 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 CSME-CI is a significant achievement in the management of 
diabetic retinopathy, laser treatment still leaves 9%-13% of patients losing more than 15 
letters of vision 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 CSME-CI is significant. 
 
1.2.3   lntravitreal Corticosteroids 
Limited clinical experience from non-randomized case series provided early evidence of 
therapeutic effect from intravitreal corticosteroids for the management of focal and diffuse 
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 Jonas et al. (2006), a single 25 mg intravitreal injection of 
triamcinolone acetonide (TA; Kenalog\) was associated with a significant mean VA 
improvement (p < 0.001) from 20/165 at baseline to 20/105 at the end of a 6-month follow- 
up. In comparison, 16 subjects observed in a "control group" that received grid laser 
photocoagulation showed no improvement in VA. 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 a third study of 12 subjects (24 


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anatomy. These "pulling" vector forces on the retina may cause and exacerbate macular 
edema. Cases such as these, in which a 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 VA improved by two or more lines in 49%-86% of 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 evidence of biologic effect in DME. Pegaptanib is an inhibitory 
aptamer, currently approved for the treatment of neovascular (wet) age-related macular 
degeneration (AMO). It is delivered as an intravitreal injection every 6 weeks. 
 
In a Phase II, double-masked, sham-controlled study of 172 subjects with DME, 73% of 
those receiving 0.3 mg pegaptanib experienced stable or improved vision (defined as < 15- 
letter loss) at Week 36 compared with 51% of those who received a sham injection (p = 
0.023) (Cunningham et al. 2005). Among subjects treated with 0.3 mg pegaptanib, 59% 
reported a vision gain of at least one line (5 letters) versus 34% of those given sham 
injections (p = 0.01O); 34% reported a vision gain of at least two lines (10 letters) versus 
10% of those given sham injections (p = 0.003); and 18% reported vision gain of at least 
three lines (15 letters) versus 7% of sham (p = 0.12). In addition, 42% of subjects receiving 
0.3 mg pegaptanib showed a decrease of at least 100 µm in mean retinal thickness 
compared with 16% of those receiving sham injections. Additionally, at the end of the study, 
only half as many subjects who received pegaptanib needed additional laser therapy 
compared with those receiving usual care (25% vs. 48%) (Cunningham et al. 2005). The 
study adds further evidence that intravitreal anti-VEGF therapy for DME is tolerated and 
could provide benefit in this disease process. 
 
1.2.6  Bevacizumab 
Bevacizumab (marked under the trade name Avastin®) is an anti-VEGF monoclonal 


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showed that three monthly injections of 0.3 mg or 0.5 mg ranibizumab were tolerated by 
subjects with CSME-CI. At 3 months, 4 of 10 subjects gained;;;: 15 letters, 5 of 10 subjects 
gained ;;;: 1 O letters, and 8 of 10 subjects gained ;;;: 1 letters. At Month 3, the 0.5 mg and 0.3 
mg ranibizumab groups demonstrated a change of+ 7.8 (A} 8.1) and+ 12 (A} 20) letters in 
mean BCVA. The mean decrease in retinal thickness of the center point of the central 
subfield was 45.3 A} 196.3 µm for the low-dose group and 197.8 A} 85.9 µm for the high- 
dose group. Although subjects in both dose arms showed improved BCVA from baseline to 
6 months on average, the anatomic and functional outcomes were better for the high-dose 
group. 
 
In another Phase I, Genentech-supported 1ST, results are available on 10 subjectswith 
CSME-CI who received the higher dose (0.5 mg) of ranibizumab with three initial monthly 
injections followed by retreatment every 2 months. Mean BCVA increased significantly to+ 
12.3 letters at 7 months, with a corresponding decrease of- 246 µmin mean foveal 
thickness. This effect was seen despite prior multiple laser treatments in 8 of the 10 
subjects and prior intravitreal triamcinolone treatment in 3 subjects. Similar to data from 
Genentech's AMO clinical trials of ranibizumab, the onset of effect occurred after the first 
dose and was sustained with monthly injections. A slight attenuation of anatomic outcome 
was seen with the 2-month retreatment interval but a return of benefit was evident after re- 
injection (Nguyen et al. 2006). 
 
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 7-8 days. Repeated intravitreal injections of ranibizumab 
can lead to detectable antibodies in serum in rabbits and cynomolgus monkeys. 


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Although there was a low rate (<4%) of arterial thromboembolic events  (ATEs)  observed  in 
the ranibizumab clinical trials there is a potential risk of ATEs following intravitreal  use  of 
inhibitors  of VEGF.   The rate of ATEs  in three  studies  (FVF2598g,  FVF2587g,  and 
FVF3192g) in the first year was1.9% of subjects in the combined  group  of subjects  treated 
with 0.3 mg or  0.5 mg ranibizumab  compared  with  1.1% of  subjects  in the control  arms  of 
the studies.  In the second  year  of Study  FVF2598g  and FVF2587g,  the rate of ATEs was 
2.6% of subjects in the combined group of those treated with 0.3 mg or 0.5 mg ranibizumab 
compared with 2.9% of subjects in the control arm. The most common non-ocular adverse 
reactions observed in.'.".. 15% of ranibizumab-treated subjects that occurred  more frequently 
than in control subjects included, nasopharyngitis, headache, and upper  respiratory  tract 
infection. 
 
The Sailor study (FVF3689g) evaluated the safety of intravitreal ranibizumab in a large 
population of subjects with CNV secondary to AMO. 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 O followed by retreatment at the 
physician's discretion, no more frequently than every 30 days. Subjects were monitored for 
safety for a total of 12 months; safety information, including both serious and nonserious 
adverse events, was collected at every clinic visit, with two formal safety visits scheduled at 
Months 6 and 12. 


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field angiography guided pan retinal photocoagulation for the treatment of CSME 
secondary to diabetes mellitus (Type 1 or Type 2). 
 
2.1 Primary Objectives 
The following primary objective measures will be evaluated: 
1) Assess number of ranibizumab injections in each of the two cohorts required 
through Month 36. 
2) Evaluate the mean change over time in ETDRS BCVA through Month 36 
3) Incidence and severity of ocular and non-ocular adverse events (AE's) through 
Month 36. 
 
2.2 Secondary Objectives 
The following secondary outcome measures will be evaluated: 
1) Percentage of patients who experience a loss of 15 or more letters from 
Baseline to Month 12, 24, and 36 in ETDRS BCVA. 
2) Determine percentage of patients who experience a gain of 15 or more letters 
from Baseline to Month 12, 24, and 36 in ETDRS BCVA. 
3) Evaluate mean change in central retinal thickness over time through Month 12, 
24, and 36 as assessed by high resolution OCT's. 
4) Percentage of patients with persistent macular edema post-intravitreal injection. 
5) Mean change in peripheral visual field as measured by Goldmann visual field at 
screen and Months 12, 24, and 36. 
 
3. STUDY DESIGN 
3.1 Description of the Study 
This study is a Phase 1/11, multicenter, randomized, study of the efficacy and safety 
of 0.3 mg ranibizumab injection monotherapy verses a duel therapy of 0.3 mg 
ranibizumab combined with ultra wide 200° field angiography guided pan retinal 
photocoagulation in patients with CSME-CI secondary to diabetes mellitus (Type 1 
or 2). 


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C). After the first session of PRP, subject's will have ultra wide 200° field 
angiography performed every 3 months to indicate areas of peripheral ischemia, 
which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 
25), preserving areas of more perfused retina. This will minimize any visual field 
loss secondary to nonselective pan-retinal photocoagulation. 
 
3.2 Rationale for Study Design 
Ranibizumab is a Fab antibody with a high affinity and specificity for VEGF-A. VEGF-A 
plays a critical role in DME as a driving factor for retinal vascular permeability, which is the 
main cause of visual impairment in patients with center-involving CSME. Based on 
nonclinical data and clinical experience in AMO and DME, the 0.5 mg and 0.3 mg 
ranibizumab doses were selected to characterize the safety and efficacy of intravitreal 
ranibizumab injections in subjects with CSME-CI. Both doses have established safety and 
efficacy profiles in subjects with neovascular AMO. The primary efficacy endpoint, the 
percentage of subjects gaining 2: 15 letters at 12 months, was chosen to demonstrate 
benefit to visual function and has been used as a functional endpoint in prior studies of 
ranibizumab in AMO. 
 
The RISE/RIDE protocol determined that only 30% of all subjects getting monthly 
intravitreal injections of 0.5 mg ranibizumab were completely dry on OCT measurement. 
The rationale of the DAVE study is the addition of utra wide 200° field angiogram guided 
pan-retinal photocoagulation will reduce the VEGF drive and increase visual function and 
decrease the total number of intravitreal injections needed in a 12-month period. 
 
Compared with prior therapies, ranibizumab is highly effective in preventing or reducing 
vision loss. In the pivotal Phase Ill clinical studies of ranibizumab for neovascular AMO, 
MARINA and ANCHOR, approximately 95% of treated patients achieved the primary visual 
acuity (VA) endpoint of losing :s; 15 letters in the Early Treatment of Diabetic Retinopathy 
Study (ETDRS) best corrected VA (BCVA), compared with 53% of sham-injected patients 
and 66% of patients treated with Visudyne®-photodynamic therapy (PDT). A significant 
number of patients treated with ranibizumab experienced durable improvement in VA. In 


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21 
 
3.3 Outcome measures 
3.3.1  Primary Outcome Measures 
The primary outcome measures for safety and tolerability are the following: 
1) Mean change over time in EDTRS BCVA through Month 36 
2) The comparative difference of total number of intravitreal injections between Cohort 
1 versus Cohort 2. 
3) Incidence and severity of ocular and non-ocular adverse events (AEs) through 
Month 36 
 
3.3.2   Secondary Outcome Measures 
1) Percentage of subjects who experience a loss of 15 or more letters from Baseline to 
Months 12, 24 and 36 in ETDRS BCVA. 
2) Percentage of subjects who experience a gain of 15 or more letters from Baseline to 
Months 12, 24 and 36 in ETDRS BCVA. 
3) Mean change in central retinal thickness over time through Months 12, 24 and 36 as 
assessed by high resolution OCT. 
4) Mean change in peripheral visual field as measured by Goldmann Visual Field 
assessed through Month 36. 
 
 
3.4  Safety Plan 
The safety and tolerability of intravitreal ranibizumab injections have been investigated in 
previous Phase I, 1/11, 111, and lllb 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 


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• 
BCVA score in the study eye of 20/32 to 20/320 approximate snellen equivalent using 
the ETDRS protocol at an initial testing distance of 4 meters, confirmed by the 
investigator. 
• 
High Definition  OCT (Spectralis)  central  retinal thickness  measurement  of ,a: 300 µm 
• 
Decrease in visual acuity is determined to be primarily the result of DME and not to 
other cause. 
• 
Ability and willingness to return for all scheduled visits and assessments. 
• 
Clear ocular media and adequate pupillary dilatation to permit good quality fundus 
photography. 
 
4.1.3   Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
General Exclusion Criteria 
• 
Pregnancy (positive pregnancy test) or lactation 
• 
Sexually active women of childbearing potential* who are unwilling to practice adequate 
contraception or abstinence during the study. (*Although no birth control method is 
100% effective, the following are considered adequate means of contraception: surgical 
sterilization, use of oral contraceptives, barrier contraception using either a condom or 
diaphragm with spermicidal gel, intrauterine devices, or contraceptive hormone implants 
or patches. A subject's primary care physician, obstetrician, or gynecologist should be 
consulted regarding an appropriate form of birth control) 
• 
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: 
o History of vitrectomy surgery in the study eye 
o Any pan-retinal photocoagulation in the study eye 
o Prior treatment with intraocular or subconjunctival steroids in the study eye 4 months 
prior to screen 


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• 
Concurrent Systemic Conditions 
o Uncontrolled blood pressure (defined as systolic > 180 mmHg and/or diastolic > 110 
mmHg while patient is seated. *If a subject's initial reading exceeds these values, a 
second reading may be taken 30 or more minutes later. If the subject's blood 
pressure needs to be controlled by antihypertensive medication, the subject can 
become eligible if medication is taken continuously for at least 30 days prior to Day 0 
o Atrial fibrillation not managed by subject's primary care physician or cardiologist 
within 3 months of screening visit 
o History of stroke within the last 3 months of screening visit 
o 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 of an investigational drug or that might affect the 
interpretation of the results of the study or renders the patient at high risk for 
treatment complications 
o Current treatment for active systemic infection 
o Active malignancy 
o History of allergy to fluorescein, not amenable to treatment 
o Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality 
to be analyzed and graded. 
o Previous participation in any studies of investigational drugs within 1 month 
preceding Day 0 (excluding vitamins and minerals) 
 
4.2  Method of Treatment Assignment 
Cohort 1: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg 
ranibizumab every 28 days(+/- 7 days). They will then be seen monthly(+/- 7 days) 
and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per 
retreatment criteria based on the evaluating Investigator's assessment of disease 
activity. 
Cohort 2: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg 
ranibizumab every 28 days(+/- 7 days). They will then be seen monthly(+/- 7 days) 
and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per 


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Following the intravitreal injection, subjects will be examined by indirect 
ophthalmoscopy to make sure there is good perfusion of retinal vessels. Subjects 
should be instructed to report any symptoms suggestive of endophthalmitis without 
delay. 
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. 
 
4.5 Study Assessments 
4.5.1  Assessments During the Treatment Period 
*Refer to Appendix A for a complete overview of study procedures. 
Vital Signs 
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 
ranibizumab. 
Ocular Assessments 
• 
BCVA at a starting distance of 4 meters at all visits 
• 
IOP measurement (perform prior to dilating eyes; the method used for a subject must 
remain consistent throughout the study) 
• 
Slit lamp examination 
• 
Dilated binocular indirect high-magnification ophthalmoscopy 
• 
Goldmann Visual Field, study eye only 
• 
Anterior chamber paracentesis (aqueous) 


29 
10 JUNE 2014 
DAVE/ML27954 
 
5) Pegaptanib sodium injection treatment in either eye 
6) SAE 
7) Any other safety concerns 
8) In the event of an adverse event in the study eye that is considered by the 
Investigator to be severs in intensity, serious consideration should be given to 
discontinuing the subject from the study. 
 
4.7 Study Discontinuation 
Retina Consultants of Houston or Genentech may terminate this study at any time. 
 
 
Reasons for terminating the study may include the following: 
1) The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to subjects 
2) Subject enrollment is unsatisfactory 
3) Data recording is inaccurate or incomplete 
 
 
4.8 Statistical Methods 
4.8.1 Analysis of the Conduct of the Study 
The analysis of data from the 36-month treatment period will be performed when all 
patients have either completed the visit at Month 36 or discontinued early from the study. 
Treatment assignment will be unmasked to the personnel performing the analysis when all 
data collected through Month 36 are in the database and the data have been cleaned and 
verified. 
 
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. 
Aggregate results of the 36-month analysis, summarized by treatment group, may be 
reported to the public before completion of the study. 


10 JUNE 2014 
DAVE/ML27954 
31 
 
This is a phase 1/2 study with 40 subjects, descriptive summaries will be provided for the 
specified co-primary endpoints, comparisons will be performed for hypothesis generating 
purposes only and no definitive inference will be made. Thus, multiplicity adjustments are 
not planned. 
A. Primary Endpoints 
1) Mean change in number of intravitreal injections through Month 36. 
2) Mean change over time in ETDRS BCVA from Baseline through Month 36. 
3) Incidence and severity of ocular and non-ocular adverse events (AEs) 
through Month 36. 
B. Secondary Endpoints 
1) Percentage of subjects who experience a loss of 15 or more letters from 
Baseline to Month 12, 24, and 36 in ETDRS BCVA. 
2) Percentage of subjects who experience a gain of 15 or more letters from 
Baseline to Month 12, 24, and 36 in ETDRS BCVA. 
3) Mean change in central retinal thickness over time through Month 12, 24, and 
36 as assessed by high resolution OCT. 
4) Mean change in peripheral visual acuity as measured by Goldmann Visual 
Field assessed through Month 36. 
 
4.8.6 Missing Data 
Analyses of efficacy and safety will be based on available cases, without imputation for 
missing values. 
 
4.8.7 Interim Analyses 
No formal schedule of interim analyses is planned. Reports of adverse events from the 
study may be reviewed and summarized periodically while the study is ongoing to ensure 
the safety of subjects. 
 
 
 
 
4.9  Data Quality Assurance 


33 
10 JUNE 2014 
DAVE/ML27954 
 
3) It requires or prolongs inpatient hospitalization. 
4) 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). 
5) It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
6) 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 Events 
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). 
 
AEs of Special Interest are defined as a potential safety problem, identified as a result of 
safety monitoring of the Product by either Genentech, Inc. or a Regulatory Authority, 
including: 
• 
Lack of Effect 
• 
Endophthalmitis 
• 
lntraocular Inflammation (including vitritis and uveitis) 
• 
Cataract (traumatic) 
• 
Increased IOP 
• 
ATE's including stroke 
• 
Retinal Pigment Tear 
• 
Retinal Detachment 
 
 
Reconciliation of Single Case Reports 
The Parties will ensure that Genentech, Inc., has adequately received all Single Case 
Reports via the exchange of a line listing documenting Single Case Reports sent by site in 
the preceding time period (e.g. monthly). Confirmation of receipt should be received within 
the time period mutually agreed upon. 


35 
10 JUNE 2014 
DAVE/ML27954 
 
 
Unexpected adverse events are those not listed in the Package Insert (P.1.) or current 
Investigator Brochure (1.8.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or 1.8. For example, 
under this definition, hepatic necrosis would be unexpected if the P.I. or 1.8. only referred to 
elevated hepatic enzymes or hepatitis. 
 
5.4 Evaluations 
Ophthalmologic evaluations will include slit lamp examination, dilated binocular indirect 
high magnification ophthalmoscopy, measurements of BCVA and intraocular pressure, and 
indirect ophthalmoscopy. (See Section 4.5 for a detailed description of the study 
assessments). 
 
5.5 Vital Signs 
Pulse and blood pressure will be measured at protocol specified study visits (See Section 
4.5). 
 
5.6 Procedures for Eliciting, Recording, and Reporting Adverse Events 
5.6.1 Eliciting Adverse Events 
A consistent methodology for eliciting AE's at all subject evaluation time points should be 
adopted. Examples or non-directive questions include: 
• 
"How have you felt since your last clinical visit?" 
• 
"Have you had any new or changed health problems since you were last here?" 
 
 
5.6.2 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
a) Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 


DAVE/ML27954 
37 
10 JUNE 2014 
 
• 
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 study drug, a report should be completed and 
expeditiously submitted to the Genentech, Inc. Follow-up to obtain the outcome of 
the pregnancy should also occur. Abortion, whether accidental, therapeutic, or 
spontaneous, should always be classified as serious, and expeditiously reported as 
an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the {study drug} should be reported as an SAE. 
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 {study drug} 
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) 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 ranibizumab will be transmitted to 
Genentech within fifteen (15) calendar days of the Awareness Date. 
• 
Serious AE reports that are unrelated to the ranibizumab will be transmitted to 
Genentech within thirty (30) calendar days of the Awareness Date. 


39 
DAVE/ML27954 
10 JUNE 2014 
 
( 
•    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/Safety/MedW  atch/HowToReport /default.htm 
 
5.6.5  Additional Reporting Requirements for IND Holders 
For Investigator-Sponsored IND Studies, some additional reporting requirements for the 
FDA apply in accordance with the guidance set forth in 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: 
( 
• 
 The Investigator is required to notify the FDA of and fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the 
use of ranibizumab. An unexpected adverse event is one that is not already described 
in the ranibizumab Investigator Brochure. Such reports are to be telephoned or faxed to 
the FDA and Genentech within 7 calendar days of first learning of the event. 
• 
The Investigator is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report (see Appendix D), of any serious, unexpected AE that is 
considered reasonably or possibly related to the use of ranibizum ab. An unexpected 
adverse event is one that is not already described in the ranibizumab 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. 


41 
DAVE/ML27954 
10 JUNE 2014 
 
Genentech Supported Research 
AE/SAE Fax Number(s): (650) 225-4682 OR (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 
 
6. INVESITGATOR   REQUIREMENTS 
6.1  Study Initiation 
 
Before the start of this study, the following documents must be on file with Retina 
Consultants of Houston or its appointed representative: 
• 
FDA correspondence letter assigning an IND number or an IND waiver letter 


43 
10 JUNE 2014 
DAVE/ML27954 
 
 
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 subject'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 reasonable foreseeable risks or discomforts to the subjects 
• 
A description of any benefits to the subjects 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 subject 
• 
A statement describing the extent, if any, to which confidential records identifying the 
subject will be maintained and that notes the possibility that the FDA and Retina 
Consultants of Houston and the drug manufacturer may inspect the records 
• 
For research involving more than minimal risk, an explanation as to whether any 
compensation and/or 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 subject's rights, and whom to contact in the event of a research- 
related injury to the subject 


45 
DAVE/ML27954 
10 JUNE 2014 
 
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 procedures. 
 
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. 
 
With 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 applicable. 
 
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 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 


10 JUNE 2014 
DAVE/ML27954 
47 
 
7. REFERENCES 
 
1. Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM. A pilot study of multiple 
intravitreal injections of ranibizumab in patients with center-involving clinically 
significant diabetic macular edema. Ophthalmology 2006;113:1706-12. 
2. Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ. Interleukin 6 induces the 
expression of vascular endothelial growth factor. J Biol Chem 1996;271:736-41. 
3. Cunningham ET Jr, Adamis AP, Altaweel M, Aiello LP, Bresler NM, D'Amico DJ, et al. 
on behalf of the Macugen Diabetic Retinopathy Study Group. A Phase II randomized 
double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, 
for diabetic macular edema. Ophthalmology 2005;112:1747-57. 
4. 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;329:977-86. 
5. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing 
intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular 
edema. Ophthalmology  2008;115:1447-9, 1449.e1-10. 
6. Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, 
Aiello LP, et al. Three-year follow-up of a randomized trial comparing focal/grid 
photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch 
Ophthalmol 2009;127:245-51. 
7. Diabetic Retinopathy Clinical Research Network Writing Committee. 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 (In-Press). 
8. Diabetic Retinopathy Study Research Group. Four risk factors for severe visual loss in 
diabetic retinopathy.  Arch Ophthalmol 1979;97:654-5. 
9. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for 
diabetic macular edema. ETDRS Study Report Number 1. Arch Ophthalmol 
1985;103:1796-806. 
10. Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques 
and clinical guidelines for photocoagulation of diabetic macular edema. ETDRS Report 


10 JUNE 2014 
DAVE/ML27954 
49 
 
results of a prospective controlled trial. Ophthalmology 2004;111:218-24. 
22. Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M. 
Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in 
human vascular smooth muscle cells. Eur J Pharmacol 1998;341:309-15. 
23. Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, et al. Vascular 
endothelial growth factor is a critical stimulus for diabetic macular edema. Am J 
Ophthalmol 2006;142:961-9. 
24. Pendergast SD, Hassan TS, Williams GA, Cox MS, Margherio RR, Ferrone PJ, et al. 
Vitrectomy for diffuse diabetic macular edema associated with a taut premacular 
posterior hyaloids. Am J Ophthalmol 2000;130:178-86. 
25. Tachi N, Ogino N. Vitrectomy for diffuse macular edema in cases of diabetic 
retinopathy. Am J Ophthalmol 1996;122:258-60. 
26. U.K. Prospective Diabetes Study Research 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 1998a;352:837-53. 
27. U.K. Prospective Diabetes Study Research Group. Tight blood pressure control and 
risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. 
Br Med J 1998b;317:703-13. 
28. van Effenterre G, Guyot-Argenton C, Guiberteau B, Hany I, Lacotte JL. Macular edema 
caused by contraction of the posterior hyaloids in diabetic retinopathy: surgical 
treatment of a series of 22 cases. J Fr Ophtalmol 1993;16:602-10. 
29. Vinores SA, Derevjanik NL, Ozaki H, Okamoto N, Campochiaro PA. Cellular 
mechanisms of blood-retinal barrier dysfunction in macular edema. Doc Ophthalmol 
1999;97:217-28. 
30. Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO. Vascular endothelial 
growth factors and angiogenesis in eye disease. Prag Retin Eye Res 2003;22:1-29. 


Schedule of Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I 
I 
I 
I 
I 
I 
I 
I 
 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
 
 
 
 
DNA Blood draw (at any 
visit) 
1. 
Measure IOP pre-dose and post-injetion 
2. 
Mandatory injection 
3. 
Injection administered on a PRN basis 
4. 
A/C tap only if subject meets retreatment criteria and is treated 
5. 
DNA blood draw at any visit 
6. 
PRP (only for subjects in cohort m2) 
 
 
 
 
 
10 JUNE 2014 
DAVE/ML27954 
51 
Visit 22 
Visit 23 
Visit24 
Visit 25 
Visit 26 
Visit 27 
Signed Informed Consent 
Medical/Ophthalmic History 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE  &Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full Ophthalmic Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
High Resolution OCT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP1 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
Visual Acuity (ETDRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
X 
X 
Goldman Visual Field 
Urine pregnancy test 
X 
X 
ultra wide 200° field 
angiography 
I
X 
X 
X 
X 
ultra wide 200° field Color 
Fundus Photos 
X 
X 
I 
X 
X 
Study Drug lnjection3 
A/C Tap 4 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
X' 
Pan Retinal Photocoagulatlon 
(PRP)' 
X 


53 
10 JUNE 2014 
DAVE/ML27954 
 
( 
Appendix B 
Pre-administration, Administration, and Post-administrationProcedures for lntravitreal 
Injections 
 
The following procedures will be implemented to minimize the risk of potential adverse 
events associated with intravitreal injections (e.g., endophthalmitis). 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, sterile ophthalmic drape, 0.5% proparacaine 
hydrochloride, 5% povidone iodine ophthalmic solution, 1% lidocaine for subconjunctival 
( 
 injection, ophthalmic antimicrobial solution (e.g., trimethoprim-polymyxin B ophthalmic 
solution, ofloxacin ophthalmic solution, ophthalmic gatifloxacin solution, ophthalmic 
moxifloxaacin solution), and injection supplies. 
 
Pre-Administration 
• 
Instill topical anesthetic. 
• 
Instill an ophthalmic antibiotic. 
• 
Subconjunctival anesthesia is optional per investigator's discretion: injection 0.5 ml of 
2% lidocaine without epinephrine at the injection site. 
• 
Disinfect the periocular skin and eyelid of the study eye. 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. At investigator's discretion, different antiseptic may be used may be used for 
periocular preparation. 
( 


55 
10 JUNE 2014 
DAVE/ML27954 
 
Appendix C 
Pan-Retinal Photocoagulation (PRP) 
 
 
Pan-Retinal Photocoagulation can be performed with topical anesthesia, subconjunctival 
anesthesia or retrobulbar anesthesia with local anesthetic as detailed below: 
 
Topical Anesthesia 
• 
Apply topical anesthetic onto the study eye 
• 
Wait 3-5 minutes and apply additional topical anesthetic onto the study eye 
• 
Allow 3-5 minutes for anesthesia to be fully effective before administering laser 
 
 
Subconjunctival Anesthesia 
• 
Apply topical anesthetic onto the study eye 
• 
In a disposable, sterile, 1cc syringe, draw up 0.5cc of 2% injectable lidocaine without 
epinephrine with a 27g, ½" needle 
• 
Replace the 27g needle with a 30g, ½" needle 
• 
The treating physician should administer the lidocaine subconjunctivally in the study eye 
• 
Allow 3-5 minutes for anesthesia to be fully effective before administering laser 
 
 
 
Retrobulbar  Anesthesia 
• 
Place the subject in a supine position 
• 
Prepare the study eye for local anesthesia by cleaning the injection area directly below 
the lower lid of the study eye with an alcohol prep pad 
• 
Apply topical anesthetic onto the study eye 
• 
In a disposable, sterile, 5cc syringe draw up 5cc of 2% injectable lidocaine without 
epinephrine with a 22g, 1 ½" needle 
• 
Replace the 22g needle with a 25g, 1 ½ needle 
• 
The treating physician should insert the needle into the retrobulbar space and inject the 
lidocaine. After withdrawing the needle, apply firm pressure to the injection site and the 
eye for approximately 2 minutes. 


( 
Appendix D 
Template for IND Safety Reports including Analysis of Similarities 
 
 
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. 
 
Previou s Reports 
The information for this section comes from Principal Investigator and the search of 
similar events. This section should be written by the responsible Principal Investigator. 
( 
Select one of the following two statements after reviewing the search of similar events 
results: 
• 
Under IND 
(insert IND#), the following IND Safety Reports of similar 
AE's have been previously submitted: 
 
MCN 
Reported Event 
Submission Date 
 
 
 
 
 
 
• 
Under IND _  _  _ 
OR 
_  _  (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 previous serious reports of the same/similar event that were considered 
( 
unrelated to the investigational product at the time of the reporting. These events would 


• 
After review of the clinical details and Investigator's comments pertaining to this AE, 
and based on experience to date, Retina Consultants of Houston 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). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
: 
'i 
 
 
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59