Clinical trial NCT02107131
Conditions: Diabetic Macular Edema
Sponsor: California Retina Consultants
Start date: 2015-03-13; Completion date: 2017-05-15
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Performance assessment testing may be a useful tool to evaluate the impact of ranibizumab on day-to-day visual function in patients with Diabetic Macular Edema (DME).

Detailed description:

Arms: arm 1: Monthly Intravitreal ranibizumab 0.3mg injections. arm 2: PRN Intravitreal ranibizumab 0.3mg injections.
Interventions: intervention 1: Intravitreal ranibizumab 0.3mg
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol:  ML29184s   
 
 
Amendment Date: 4December2015 
Lucentis IST Program 
 
PROTOCOL 
STUDY TITLE: 
Evaluation of ReAding Speed, Contrast 
Sensitivity, and Work Productivity in Working 
Individuals with Diabetic Macular Edema 
Following Treatment with Intravitreal 
Ranibizumab (ERASER Study) 
STUDY DRUG 
Recombinant humanized anti-VEGF 
monoclonal antibody fragment (rhuFab V2 
[ranibizumab]) 
SPONSOR 
California Retina Research Foundation 
525 E. Micheltorena Street, Suites A & D 
Santa Barbara, California, United States 93103 
NCT NUMBER: 
NCT02107131 
INVESTIGATOR 
Nathan Steinle, MD 
SUB-
INVESTIGATORS 
Robert Avery, MD 
Ma’an Nasir, MD 
Dante Pieramici, MD 
Alessandro Castellarin, MD 
Robert See, MD 
Stephen Couvillion, MD 
Dilsher Dhoot, MD 
 
DATE: 
12/4/2015 
AMENDMENT: 
3 


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Lucentis IST Program 
1. 
BACKGROUND 
1.1 
PATHOPHYSIOLOGY 
 
Diabetic retinopathy is the leading cause of blindness associated with retinal 
vascular disease.  Macular edema is a major cause of central vision loss in 
patients presenting with diabetic retinopathy. The prevalence of diabetic 
macular edema after 15 years of known diabetes is approximately 20% in 
patients with type 1 diabetes mellitus (DM), 25% in patients with type 2 DM 
who are taking insulin, and 14% in patients with type 2 DM who do not take 
insulin.  
 
Breakdown of endothelial tight junctions and loss of the blood-retinal barrier 
between the retinal pigment epithelium and choriocapillaris junction lead to 
exudation of blood, fluid, and lipid leading to thickening of the retina.  When 
these changes involves or threatens the fovea, there is a higher risk of central 
vision loss.  Functional and eventual structural changes in the blood-retinal 
barrier as well as reduced retinal blood flow leads to the development of 
hypoxia.  These changes may result in upregulation and release of vascular 
endothelial growth factor (VEGF), a 45 kD glycoprotein. Vinores and 
colleagues showed through immunohistochemistical staining, elevated VEGF 
levels in the retinal neurons and retinal pigment epithelium of patients with 
diabetic retinopathy. The upregulation of VEGF may further increase retinal 
edema as VEGF has been shown to be a potent factor increasing retinal 
vascular permeability. 
 
1.2 
TREATMENT  
Laser photocoagulation 
Focal photocoagulation treatment for diabetic macular edema involves direct 
treatment of discrete lesions or areas of diffuse leakage in areas surrounding 
the center of the macula.  The aim of focal photocoagulation is to close leaking 
microaneuryms, intraretinal vascular abnormalities or small neovascular fronds 


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identified on fluorescein angiography.  Grid photocoagulation is applied to 
areas of retinal thickening or areas of non-perfusion or capillary drop out. 
In the Early Treatment of Diabetic Retinopathy Study (ETDRS) and the more 
recent Diabetic Retinopathy Clinical Research Network (DRCRnet) study, focal 
photocoagulation of eyes with DME reduced the risk of moderate central vision 
loss after initiation of treatment. However, a majority of the eyes in each study 
continued still had macular edema and retinal thickening after one year. 
The mechanism of action of focal photocoagulation is not fully understood and 
the laser energy can cause thermal injury to the retina leading to expanded 
atrophy larger than the intended laser spot size.  This leads to loss of central 
vision, central scotoma and decreased color vision.  Modified treatment 
parameters and the advent of new lasers have minimized risk of unnecessary 
thermal injury to the viable retinal tissue.   
Other Treatment 
Intravitreal steroid medication has been investigated in observational and 
clinical trials with good outcomes in terms of reduction in macular edema 
associated with diabetic retinopathy. However, vision threatening side-effects 
such as increased cataract formation and elevated intraocular pressure were 
noted in subjects receiving intraocular steroids.   
Pars plana vitrectomy has been used to remove vitreomacular traction that 
may contribute to the existing macular edema in patients with diabetic 
retinopathy.  While this surgical intervention may be effective at reducing 
macular swelling, the procedure is an invasive intervention with extensive 
recovery time. 
 
1.3 
RANIBIZUMAB AND DIABETIC MACULAR EDEMA 
Ranibizumab (rhuFab V2), a monoclonal anti-VEGF antibody fragment that 
blocks all active isoforms of VEGF-A, is a potent inhibitor of vascular 
permeability, with the potential to reduce retinal vascular leakage and diminish 
macular edema.  In addition, as an anti-VEGF agent, it may also inhibit 
neovascularization, a frequent complication of proliferative diabetic 
retinopathy.  Intravitreal use of ranibizumab does carry the risk of intraocular 
infection, but the risk of glaucoma or cataract formation is lower compared to 


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triamcinolone use, making it a potentially safer pharmacologic treatment for 
diabetic macular edema. 
 
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 approximately 9 days.  Repeated 
intravitreal injections of ranibizumab can lead to detectable antibodies in 
serum in rabbits and cynomolgus monkeys. 
 
1.4.2 Nonclinical Toxicology 
A series of nonclinical studies of ranibizumab administered by intravitreal 
injection to cynomolgus monkeys have been performed (details regarding 
study design and results can be found in the Investigator Brochure). 
 
1.4.3 Nonclinical Data Supporting the Anti-Edema Activity of Ranibizumab 
In Studies 01-401E-1757 and 01-401G-1757, the effect of ranibizumab on 
vascular leakage was explored using a modified Miles assay in the guinea pig.  
Ranibizumab demonstrated a concentration-dependent effect of blunting the 
vascular permeability induced by VEGF.  These results are consistent with the 
decrease in retinal vascular permeability as observed on optical coherence 
tomography (OCT) and fluorescein angiography in AMD and diabetic macular 
edema studies and further support the rationale for the use of ranibizumab in 
CRVO and BRVO, in which vascular permeability plays a significant role in the 
pathology   
 


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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 excipients 
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 30 minutes of intravitreal injection with 
ranibizumab.  Therefore, IOP as well as perfusion of the optic nerve head should 
be monitored and managed appropriately.  Serious adverse events related to the 
injection procedure have occurred in <0.1% of intravitreal injections include 
endophthalmitis, rhegmatogenous retinal detachment, and iatrogenic traumatic 
cataract.  Other serous ocular adverse events observed among ranibizumab-
treated subjects and occurring in <2% of subjects included intraocular 
inflammation and increased IOP.  The most common adverse reactions (reported 
> 6% higher in ranibizumab-treated subjects 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 was 1.9% of subjects in 
the combined group of subjects treated with 0.3 mg or 0.5 mg ranibizumab 
compared with 1.1% of subjects in the control arms of the studies.  In the second 
year of Study FVF2598g and FVF2587g, the rate of ATEs was 2.6% of subjects 
in the combined group of those treated with 0.3 mg or 0.5 mg ranibizumab 
compared with 2.9% of subjects in the control arm.  The most common non-
ocular adverse reactions observed in > 15% of ranibizumab-treated subjects that 
occurred more frequently than in control subjects included, nasopharyngitis, 
headache, and upper respiratory tract infection. 
  
The Sailor study (FVF3689g) evaluated the safety of intravitreal ranibizumab in a 
large population of subjects with CNV secondary to AMD.  Subjects in Cohort 1 


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(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 irdocylitis 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 


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hemorrhage was similar across Cohort 1 dose groups.  APTC ATEs, including 
vascular and unknown deaths, nonfatal MI, and nonfatal cardiovascular 
accidents, were similar across dose groups.  During the 12-month study period, 
0.7% of subjects in the 0.3-mg group and 1.2% of subjects in the 0.5-mg group 
suffered a stroke.  The number of vascular deaths and deaths due to unknown 
cause did not differ across dose groups.  Rates of key non-ocular SAEs in Cohort 
2 were generally lower than those in Cohort 1. 
 
Refer to the Ranibizumab Investigator Brochure or Lucentis® Package Insert for 
additional details regarding clinical safety experience with ranibizumab. 
 
 
2. 
OBJECTIVES 
 
2.1 Primary Objectives 
 
 
- 
To determine the mean change in maximum reading speed on 
MNREAD reading acuity charts (binocular reading) and Radner reading 
cards (monocular reading) from baseline to Months 3, 6, and 12. 
 
 
2.2 Secondary Objectives 
 
- 
To measure the mean change in contrast sensitivity scores on Pelli-
Robson charts from baseline to Months 3, 6, and 12. 
 
- 
To evaluate the mean change in work productivity and activity 
impairment from baseline to Month 1, Month 3, and Month 12. 
 
- 
To measure and compare the smallest print size that a subject can 
resolve on MNREAD reading acuity charts (binocular reading) and 
Radner reading cards (monocular reading) from baseline to Months 3, 
6, and 12. 
 
 
- 
To determine the mean change in best-corrected visual acuity in each 
subgroup, a) monthly treatment group and b) PRN treatment group, on 
ETDRS visual acuity chart at a starting distance of 4 meters from 
baseline to Month 12. 
 
- 
To determine the mean change in central 1mm subfield retinal 
thickness from baseline to Months 3, 6, and12.  
 


Protocol:  ML29184s   
 
 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an open-label, Phase I/II study of intravitreally administered 
ranibizumab 0.3mg in subjects with clinical, angiographic, and ocular 
coherence tomography (OCT) evidence of diabetic retinopathy with associated 
diabetic macular edema (DME). Patients do not need to be treatment naïve, 
however there must be a minimum of a 120 day washout in the study eye(s) 
from any prior intraocular corticosteroids or anti-VEGF treatment. Fourty 
patients will be enrolled in this study.  
Consented, enrolled subjects will be randomized 1:1 to one of two groups a) 
Monthly treatment group [n=20] or b) as needed treatment group (PRN) 
[n=20], prior to treatment at the baseline study visit. Each group will receive 
monthly injections for the first 6 visits. At month 6, the randomized phase of 
the protocol will begin. This study will enroll 1/2 of subjects with bilateral DME, 
which will be evenly distributed to the 2 treatment groups (10 subjects in the 
Monthly group and 10 subjects in the PRN group) to equally assess reading 
speed and contrast sensitivity with bilateral disease in both groups. All 
subjects enrolled will be working (at least part time).  
All subjects will receive multiple open-label intravitreal injections of 0.3 mg 
ranibizumab administered every 30 days (±7 days) for 6 injections during the 
mandatory treatment phase (Day 0, and Months 1, 2, 3, 4, & 5).  Subjects in 
the monthly treatment group will continue to receive intravitreal injections of 
0.3mg ranibizumab administered every 30 days (±7 days) through 11 months. 
No study treatment will be administered at the exit visit. Subjects in the as 
needed treatment group (PRN) will receive intravitreal injections of 
ranibizumab 0.3mg if there is evidence of macular edema on spectral domain 
optical coherence tomography.  In subjects with bilateral DME, both eyes will 
follow identical treatment regimen (i.e. both eyes will receive monthly dosing if 
the subject is randomized to monthly treatment group). 
All subjects will make monthly visits for 12 months for evaluation of safety and 
efficacy.  All subjects will have their first injection of ranibizumab on Day 0 and 
may undergo a safety visit one week (±2 days) after the first injection, at the 
discretion of their study doctor.  At subsequent visits, the subject will have a 


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safety evaluation at the monthly scheduled follow-up visit prior to any 
intravitreal injection.  Subjects will be instructed to contact study personnel 
after each injection to report any decreased vision, pain or unusual or new 
ocular symptoms. 
 
3.2 
RATIONALE FOR STUDY DESIGN 
Treatment of diabetic macular edema (DME) with intravitreal ranibizumab has been 
shown reduce retinal thickening and improve visual acuity (RIDE/RISE, 2012).  
However, very few studies have directly assessed the benefits of ranibizumab on 
patient visual function in eyes with DME. Performance assessment testing including 
reading speed, contrast sensitivity and work productivity has been used to show 
functional visual gain in eyes with macular edema secondary to retinal vein occlusion 
following ranibizumab treatment (Suner, 2013).  Thus, performance assessment 
testing may be a useful tool to evaluate the impact of ranibizumab on day-to-day 
visual function in patients with DME. 
 
3.3 
OUTCOME MEASURES 
3.3.1 Primary Outcome Measures 
• Change in reading speed (as assessed by number of characters read per 
minute on MNREAD and Radner reading charts) at Months 3, 6, and Month 
12 compared to baseline. 
 
3.3.2 Secondary Outcome Measures 
• Change in work productivity (per the WPAI questionnaire - Appendix E) at 
Months 3, 6, and 12 compared to baseline. 
• Best corrected visual acuity (BCVA), as assessed by the number of letters 
read correctly on the ETDRS eye chart at a starting test distance of 
4 meters, at Month 3 and Month 12. 
• Incidence and severity of ocular and systemic adverse events, as identified 
by ophthalmic examination, subject reporting, and physical examination  
 
 
3.4 
SAFETY PLAN 
The safety assessments to be conducted for this study are listed in Section 4.5 
and Appendix A. 


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All adverse events (serious and nonserious) will be recorded on Case Report 
Forms (CRFs) for the duration of the study.   
The major safety issues concerning administration of ranibizumab are related 
to the intraocular injection, and include risks of endophthalmitis, retinal break 
and detachment, cataract formation, intraocular inflammation, intraocular 
hemorrhage, and intraocular pressure elevation.  Previous Phase III clinical 
trials of anti-VEGF agents using proper sterile technique have demonstrated 
an extremely low incidence of such events (< 0.2%/per injection)  
After each injection of ranibizumab, study staff will confirm patient is at least 
able to count fingers in each treated eye. Patients may remain at the office for 
additional time, at the discretion of the treating physician for an intraocular 
pressure check, or examination of retinal artery perfusion post injection.  
Following the procedure, subjects will be instructed to use topical antibiotics at 
the discretion of the treating physician, and to contact the clinic should they 
experience any symptoms of decreased vision or increasing pain. 
The investigator will temporarily withhold further study drug injection for 
patients experiencing ocular or non-ocular adverse events thought to be 
related to the drug or its administration.  In the event a subject develops an 
adverse event that is severe in intensity (e.g. endophthalmitis, 
rhegmatogenous retinal detachment), study discontinuation will be considered 
for that patient.  As with any study of an investigational product, the 
investigator, patient, or sponsor may request that a subject withdraw from 
treatment or from the study for safety reasons at any time.  Subjects who are 
discontinued from study treatment may continue to undergo scheduled study 
visits if they so choose.   
The investigators and study sponsors will monitor all adverse events and the 
FDA will be notified of any interruption in enrollment or change in the conduct 
of the study.  
Given the small number of patients enrolled in this trial, conclusions regarding 
safety in this subgroup of patients will be limited.  However, accumulating data 
from a number of other trials utilizing intravitreal ranibizumab should provide 
better estimates of the incidence of various ocular and non-ocular 


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complications.  This information will be monitored by the investigators and 
information provided to study participants as necessary. 
 
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 
Describe how subjects in this study will be selected (i.e., who will comprise the 
study population). 
 
40 subjects from approximately 6 sites in the United States will be enrolled.   
Eligible subjects will be administered and provided with a copy of informed 
consent.   
 
(See Appendix A, the study flow chart, for screening assessments.) 
 
 
4.1.2 Inclusion Criteria 
Subjects will be eligible if the following criteria are met:  
 
• Ability to provide written informed consent and comply with study 
assessments for the full duration of the study 
• Age 18 ≤ years and ability to be employed at the baseline study visit 
• Diagnosis of diabetes mellitus (type 1 or 2) 
o Any one of the following will be considered to be sufficient 
evidence that diabetes is present: 
▪ Current regular use of insulin for treatment of diabetes 
▪ Current regular use of oral anti-hyperglycemia agent for the 
treatment of diabetes 


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• Clinical evidence of retinal thickening due to macular edema involving the 
center of the macula, associated with diabetic retinopathy.  
• Central diabetic macular edema present on clinical examination or or 
evidence indicating disease activity on spectral domain OCT. 
• Visual acuity score greater than or equal to 19 letters (20/400) and less than or 
equal to 73 letters (20/40) by the ETDRS visual acuity protocol.  
• Media clarity, pupillary dilation and patient cooperation sufficient to allow 
OCT testing and retinal photography 
 
 
4.1.3 Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this 
study:  
 
• Pregnancy (positive pregnancy test) or known to be pregnant; also pre-
menopausal women not using adequate contraception. 
• Participation in another ocular investigation or trial simultaneously 
• Blood pressure > 180/110 (systolic above 180 OR diastolic above 110) 
• Any condition that, in the opinion of the investigator, would preclude 
participation in the study (e.g. chronic alcoholism, drug abuse) 
• Evidence of vitreoretinal interface abnormality after ocular exam or OCT 
that may be contributing to the macular edema 
• An eye that, in the investigator’s opinion, has no chance of improving in 
visual acuity following resolution of macular edema (e.g. presence of  
subretinal fibrosis or geographic atrophy) 
• Presence of another ocular condition that may affect the visual acuity or 
macular edema during the course of the study (e.g. AMD, uveitis, Irvine-
Gas) 
• Evidence of active neovascularization of the iris or retina  
• Evidence of central atrophy or fibrosis in the study eye 
• Presence of substantial cataract, one that might decrease the vision by 3 
or more lines of vision at any time during the study 
• Use of intraocular or periocular corticosteroids in the study eye(s) within 
120 days prior to enrollment 


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• Use of anti-angiogenic drugs in the study eye i.e. pegaptanib sodium, 
bevacizumab, ranibizumab, aflibercept within 120 days prior to enrollment 
• History of vitreous surgery in the study eye 
• History of cataract surgery within 3 months of enrollment. 
• History of YAG capsulotomy within 2 months of enrollment.  
• Visual acuity <20/400 in the fellow eye 
• Uncontrolled glaucoma (pressure >30) despite treatment with glaucoma 
medications. 
• History of cerebral vascular accident or myocardial infarction within 3 
months prior to Day 0. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
After informed consent is obtained, screening procedures have been completed and 
the subject meets all eligibility criteria, all patients will receive treatment with study 
drug. All patients will receive six consecutive intravitreal injections of 0.3 mg 
ranibizumab. Subjects in the monthly treatment group will continue to receive 
intravitreal ranibizumab 0.3 mg at each monthly study visit through Month 11. No 
study treatment is administered at the month 12 visit. Beginning at Month 6, subjects 
in the as needed treatment group will receive additional intravitreal injections of 
ranibizumab 0.3 mg if there is evidence of disease activity documented on SDOCT 
scans.  
 
4.3 
STUDY TREATMENT 
4.3.1 Formulation 
0.3-mg dose 
Ranibizumab is formulated as a sterile solution aseptically filled in a sterile, 2-mL 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.  Each vial contains no preservative and is suitable 
for single use only. 
 
4.3.2 Dosage, Administration, and Storage 
a. Dosage 


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Ranibizumab will be administered to all subjects in a single dose regimen of 
0.3 mg every month for the first six months (Day 0, and Months 1, 2, 3, 4, & 5).  
Beginning at Month 6, subjects assigned to the as needed treatment group 
will be eligible to receive additional 0.3 mg ranibizumab to treat recurrent 
macular edema for an additional 6 months.  The intent is to administer 
additional ranibizumab treatment if there is evidence of disease activity 
documented on SDOCT (e.g., intra-retinal fluid, subretinal fluid and/or cystic 
changes).   
Subjects assigned to the monthly treatment group will continue to receive 
monthly intravitreal injections of 0.3 mg ranibizumab administered every 30 
days (±7 days) at each study visit through month 11, for a total of 12 
intravitreal injections of 0.3 mg ranibizumab.   
b. Administration 
*See Appendix B for detailed pre-injection procedures. 
 
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. 
Subjects cannot receive any other anti-VEGF therapy (other than ranibizumab) 
in either eye.  
4.5 
STUDY ASSESSMENTS 
4.5.1 Assessments during the Treatment Period 
All subjects will complete an ophthalmic examination (including intraocular pressure, 
slit-lamp and indirect ophthalmoscopy), standardized ETDRS vision testing 


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(monocular then repeat testing under binocular conditions), and spectral-domain OCT 
testing will be conducted at each monthly visit during the study from Baseline to 
Month 12 (the OCT model used on a patient must remain consistent throughout the 
study).  At Baseline/Day 0, Months 6 and 12, fundus photographs and fluorescein 
angiograms will be obtained for all subjects.  
 
All subjects will be administered reading speed tests at baseline, Month 3, Month 6, 
and Month 12 using the MNREAD reading acuity charts and Radner reading cards 
(Appendix D). MNREAD reading acuity charts will be administered under binocular 
conditions.  The Radner reading cards will be administered with the subject using one 
eye at a time.  Contrast sensitivity testing using Pelli-Robson charts will be 
administered to all subjects at baseline, Month 3, Month 6, and Month 12.  The Pelli-
Robson charts will be viewed monocularly.    
 
The Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem V2.0 (WPAI:SHP) (see Appendix E) will be administered to each subject at 
baseline, Month 3, Month 6, and Month 12 to assess work productivity and activity 
impairment due to vision loss associated with diabetic macular edema. 
 
Data will be collected from both eyes including intraocular pressure, ETDRS vision 
testing, and spectral-domain OCT testing. All testing will be done prior to 
administration of intravitreal injections. 
 
 
4.5.2 Early Termination Assessments 
Subjects who withdraw from the study prior to completion should return for an 
early termination evaluation within 30 days ( 7 days) following the last 
injection/study visit for monitoring of all adverse events (serious and 
nonserious).   
 
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 of the following reasons: 
if it is in the best interest of the subject, intercurrent illness, adverse events, or 


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worsening condition.  The California Retina Research Foundation or Nathan 
Steinle, 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 may re-enter the study at 
the discretion of the study doctor. 
Reasons for subject discontinuation may include, but are not limited to, the 
following: 
• 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 
• SAE 
• Any other safety concerns 
In the event of an adverse event in the study eye that is considered by the 
investigator to be severe in intensity, serious consideration should be given to 
discontinuing the subject from the study.   
 
4.7 
STUDY DISCONTINUATION 
This study may be terminated by California Retina Research Foundation or 
Genentech at any time.  Reasons for terminating the study may include the 
following: 
• The incidence or severity of adverse events in this or other studies 
indicates a potential health hazard to subjects 
• Subject enrollment is unsatisfactory 
• Data recording is inaccurate or incomplete   
 
4.8 
STATISTICAL METHODS 
4.8.1 Analysis of the Conduct of the Study 
There is no formal sample size calculation in this exploratory pharmacokinetic 
study.  As this is a pilot study, a sample size of 40 patients is chosen, making 


Protocol:  ML29184s   
 
 
Amendment Date: 4December2015 
Lucentis IST Program 
sure that it is feasible to conduct the study and logistically to complete the 
study within 1-2 years.   
 
4.8.2 Safety Analyses 
Any adverse events, laboratory assessments, physical examinations, vital 
signs, ocular examinations and measurements from all 40 subjects will be 
utilized to summarize safety data for this pilot study. 
4.8.3 Efficacy Analyses 
There is no formal sample size calculation in this exploratory analysis of 
intraocular fluid, serum and plasma samples.  A sample size of 40 patients was 
chosen, making sure that it is feasible logistically to conduct and to complete 
the study within two years. 
a. Primary Endpoint 
The primary endpoint is the mean change in maximum reading speed from 
baseline to Months 3, 6, and 12, based on MNREAD reading acuity charts 
(binocular reading) and Radner reading cards (monocular reading). 
b. Secondary Endpoints 
 
The secondary endpoints include the following: 
• Mean change in work productivity from baseline (per the WPAI:SH 
questionnaire) to Months 3, 6, an 12. 
• Mean change in contrast sensitivity from baseline to Months 3, 6, and 
12 based on Pelli-Robson charts 
• Mean change in best-corrected visual acuity from baseline to Month 
12 based on ETDRS visual acuity charts. 
• Mean change in central 1mm subfield thickness from baseline to 
Months 3, 6, and Month 12. 
 
4.8.4 Missing Data 
Analyses will be done two ways: one including all subjects who were enrolled 
and one only including subjects that were not discontinued and did not miss 2 
or more visits in a row or 3 visits total will be assessed. Analyses of efficacy 
and safety will be based on available cases, without imputation for missing 
values.    


Protocol:  ML29184s   
 
 
Amendment Date: 4December2015 
Lucentis IST Program 
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.     
 
 


Protocol:  ML29184s   
 
 
Amendment Date: 4December2015 
Lucentis IST Program 
REFERENCES 
Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, 
Iwamoto MA, Park JE et al: Vascular endothelial growth factor in ocular fluid of patients with 
diabetic retinopathy and other retinal disorders. The New England journal of medicine 1994, 
331(22):1480-1487. 
 
Arevalo JF, Sanchez JG, Wu L, Maia M, Alezzandrini AA, Brito M, Bonafonte S, Lujan S, 
Diaz-Llopis M, Restrepo N et al: Primary intravitreal bevacizumab for diffuse diabetic 
macular edema: the Pan-American Collaborative Retina Study Group at 24 months. 
Ophthalmology 2009, 116(8):1488-1497, 1497 e1481. 
 
Avery RL: Regression of retinal and iris neovascularization after intravitreal bevacizumab 
(Avastin) treatment. Retina 2006, 26(3):352-354. 
 
Chen Y, Wiesmann C, Fuh G, Li B, Christinger HW, McKay P, de Vos AM, Lowman HB: 
Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-
matured Fab in complex with antigen. Journal of molecular biology 1999, 293(4):865-881. 
 
Chong V: Biological, preclinical and clinical characteristics of inhibitors of vascular 
endothelial growth factors. Ophthalmologica Journal international d'ophtalmologie 
International journal of ophthalmology Zeitschrift fur Augenheilkunde 2012, 227 Suppl 1:2-
10. 
 
Diabetic Retinopathy Clinical Research N, Scott IU, Edwards AR, Beck RW, Bressler NM, 
Chan CK, Elman MJ, Friedman SM, Greven CM, Maturi RK et al: A phase II randomized 
clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology 2007, 
114(10):1860-1867. 
 
Diabetic Retinopathy Clinical Research N, Elman MJ, Qin H, Aiello LP, Beck RW, Bressler 
NM, Ferris FL, 3rd, Glassman AR, Maturi RK, Melia M: Intravitreal ranibizumab for diabetic 


Protocol:  ML29184s   
 
 
Amendment Date: 4December2015 
Lucentis IST Program 
macular edema with prompt versus deferred laser treatment: three-year randomized trial 
results. Ophthalmology 2012, 119(11):2312-2318. 
 
Do DV, Nguyen QD, Khwaja AA, Channa R, Sepah YJ, Sophie R, Hafiz G, Campochiaro PA, 
Group R-S: Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and 
the need for prolonged frequent treatment. JAMA ophthalmology 2013, 131(2):139-145. 
 
Ehlers JP, Spirn MJ, Shah CP, Fenton GL, Baker PS, Regillo CD, Ho AC: Ranibizumab for 
exudative age-related macular degeneration in eyes previously treated with alternative 
vascular endothelial growth factor inhibitors. Ophthalmic surgery, lasers & imaging : the 
official journal of the International Society for Imaging in the Eye 2010, 41(2):182-189. 
 
Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL, 3rd, Friedman SM, Glassman AR, Scott 
IU, Stockdale CR, Sun JK et al: Expanded 2-year follow-up of ranibizumab plus prompt or 
deferred laser or triamcinolone plus prompt laser for diabetic macular edema. 
Ophthalmology 2011, 118(4):609-614. 
 
Ferrara N: Vascular endothelial growth factor: basic science and clinical progress. Endocrine 
reviews 2004, 25(4):581-611. 
 
Ferrara N, Damico L, Shams N, Lowman H, Kim R: Development of ranibizumab, an anti-
vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-
related macular degeneration. Retina 2006, 26(8):859-870. 
 
Kent JS, Iordanous Y, Mao A, Powell AM, Kent SS, Sheidow TG: Comparison of outcomes 
after switching treatment from intravitreal bevacizumab to ranibizumab in neovascular age-
related macular degeneration. Canadian journal of ophthalmology Journal canadien 
d'ophtalmologie 2012, 47(2):159-164. 
 


Protocol:  ML29184s   
 
 
Amendment Date: 4December2015 
Lucentis IST Program 
Krohne TU, Liu Z, Holz FG, Meyer CH: Intraocular pharmacokinetics of ranibizumab 
following a single intravitreal injection in humans. American journal of ophthalmology 2012, 
154(4):682-686 e682. 
 
Massin P, Bandello F, Garweg JG, Hansen LL, Harding SP, Larsen M, Mitchell P, Sharp D, 
Wolf-Schnurrbusch UE, Gekkieva M et al: Safety and efficacy of ranibizumab in diabetic 
macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, 
multicenter phase II study. Diabetes care 2010, 33(11):2399-2405. 
 
Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, Sutter F, 
Simader C, Burian G, Gerstner O et al: The RESTORE study: ranibizumab monotherapy or 
combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 
2011, 118(4):615-625. 
 
Mordenti J, Cuthbertson RA, Ferrara N, Thomsen K, Berleau L, Licko V, Allen PC, Valverde 
CR, Meng YG, Fei DT et al: Comparisons of the intraocular tissue distribution, 
pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus 
monkeys following intravitreal administration. Toxicologic pathology 1999, 27(5):536-544. 
 
Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle 
AC, Hopkins JJ, Rubio RG, Ehrlich JS; RISE and RIDE Research Group. Ophthalmology. 
(2012) Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: 
RISE and RIDE. Apr;119(4):789-801. doi: 10.1016/j.ophtha.2011.12.039. Epub 2012 Feb 11. 
Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do DV, 
Campochiaro PA: Vascular endothelial growth factor is a critical stimulus for diabetic macular 
edema. American journal of ophthalmology 2006, 142(6):961-969. 
 
Nguyen QD, Shah SM, Khwaja AA, Channa R, Hatef E, Do DV, Boyer D, Heier JS, Abraham 
P, Thach AB et al: Two-year outcomes of the ranibizumab for edema of the mAcula in 
diabetes (READ-2) study. Ophthalmology 2010, 117(11):2146-2151. 
 


Protocol:  ML29184s   
 
 
Amendment Date: 4December2015 
Lucentis IST Program 
Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle 
AC, Hopkins JJ et al: Ranibizumab for diabetic macular edema: results from 2 phase III 
randomized trials: RISE and RIDE. Ophthalmology 2012, 119(4):789-801. 
 
Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study 
report number 1. Early Treatment Diabetic Retinopathy Study research group. Archives of 
ophthalmology 1985, 103(12):1796-1806. 
 
Rajendram R, Fraser-Bell S, Kaines A, Michaelides M, Hamilton RD, Esposti SD, Peto T, 
Egan C, Bunce C, Leslie RD et al: A 2-year prospective randomized controlled trial of 
intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular 
edema: 24-month data: report 3. Archives of ophthalmology 2012, 130(8):972-979. 
 
Soheilian M, Ramezani A, Bijanzadeh B, Yaseri M, Ahmadieh H, Dehghan MH, Azarmina M, 
Moradian S, Tabatabaei H, Peyman GA: Intravitreal bevacizumab (avastin) injection alone or 
combined with triamcinolone versus macular photocoagulation as primary treatment of 
diabetic macular edema. Retina 2007, 27(9):1187-1195. 
 
Soheilian M, Ramezani A, Obudi A, Bijanzadeh B, Salehipour M, Yaseri M, Ahmadieh H, 
Dehghan MH, Azarmina M, Moradian S et al: Randomized trial of intravitreal bevacizumab 
alone or combined with triamcinolone versus macular photocoagulation in diabetic macular 
edema. Ophthalmology 2009, 116(6):1142-1150. 
 
Solaiman KA, Diab MM, Abo-Elenin M: Intravitreal bevacizumab and/or macular 
photocoagulation as a primary treatment for diffuse diabetic macular edema. Retina 2010, 
30(10):1638-1645. 
 
Stewart MW, Rosenfeld PJ, Penha FM, Wang F, Yehoshua Z, Bueno-Lopez E, Lopez PF: 
Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal 
ranibizumab, bevacizumab, and aflibercept (vascular endothelial growth factor Trap-eye). 
Retina 2012, 32(3):434-457. 


Protocol:  ML29184s   
 
 
Amendment Date: 4December2015 
Lucentis IST Program 
 
Suñer IJ, Bressler NM, Varma R, Lee P, Dolan CM, Ward J, Colman S, Rubio RG. Reading 
Speed Improvements in Retinal Vein Occlusion After Ranibizumab Treatment. JAMA 
Ophthalmol. 2013 May 9:1-6. doi: 10.1001/jamaophthalmol.2013.114. [Epub ahead of print] 
 
Wykoff CC, Brown DM, Chen E, Major JC, Croft DE, Mariani A, Wong TP, Group SS: SAVE 
(Super-dose anti-VEGF) trial: 2.0 mg ranibizumab for recalcitrant neovascular age-related 
macular degeneration: 1-year results. Ophthalmic surgery, lasers & imaging retina 2013, 
44(2):121-126. 
 
 


Protocol:  ML29184s   
 
 
Amendment Date: 4December2015 
Lucentis IST Program 
APPENDIX A 
 
 
 
Assessments During Treatment Period 
Randomized Treatment Period 
Study Flowchart  
Screen/Day 0 
Month 
1 
Month 
2 
Month 
3 
Month 
4 
Month 
5 
Month 
6 
Month 
7 
Month 
8 
Month 
9 
Month 
10 
Month 
11 
Month 
12 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Vital Signs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Ocular History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
WPAI:SHP 
X 
  
  
 X 
  
  
X  
  
  
  
  
  
X  
Refractionb 
X 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
BCVA (4m starting 
distance; monocular then 
repeat binocular) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Indirect Ophthalmoscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fundus Photos 
X 
  
  
 
  
  
X 
  
  
 
  
  
X 
FA 
X 
  
  
 
  
  
X 
  
  
 
  
  
X 
SD-OCT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intraocular Pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MNREAD (binocular) 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Radner 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Pelli-Robson 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Ranibizumab 0.3mg 
X 
X 
X 
 X 
X 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aSubjects assigned to as needed treatment group will receive intravitreal ranibizumab 0.3mg if macular edema is present on SDOCT. Subjects assigned to monthly treatment group 
will receive intravitreal ranibizumab 0.3mg. 
bRefraction required only at baseline, and visits where BCVA decreases by 10 or more letters 


Protocol:  ML29184s   
 
 
Amendment Date: 4December2015 
Lucentis IST Program