REtinal Vein OccLUsion Treatment With Scatter Laser Guided by UWFA in combiNAtion With Ranibizumab Study

SUBJECTS Subject Selection Twenty subjects from a single site in the United States will be
enrolled. Eligible subjects will have provided informed consent. (See Appendix A, the
study flow chart, for screening assessments.)

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

Disease related considerations:

Study eye with macular edema secondary to branch retinal vein occlusion characterized by:

Fovea-involved macular edema of less than 12 months peripheral nonperfusion defined as at
least 5 disc areas of contiguous nonperfusion on ultra-widefield fluorescein angiography
absence of macular traction on clinical exam, UWFA, and OCT.

Study eye with best corrected visual acuity between 20/40 (≤ 73 letters on ETDRS chart) and
20/320 (≥ 19 letters on ETDRS chart) Other considerations Patient able to complete all study
visits

Exclusion Criteria

Subjects who meet any of the following criteria will be excluded from this study:

Pregnancy (positive pregnancy test) or lactation. Premenopausal women not using adequate
contraception. The following are considered effective means of contraception: surgical
sterilization or use of oral contraceptives, barrier contraception with either a condom or
diaphragm in conjunction with spermicidal gel, an IUD, or contraceptive hormone implant or
patch.

Prior enrollment in the study 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 Therapy with
intravitreal triamcinolone, pegaptanib, ranibizumab, or bevacizumab within the previous 3
months Previous macular or panretinal scatter laser photocoagulation Previous pars plana
vitrectomy Visually-significant significant cataracts as primary reason for vision loss
Myocardial infarction or cerebrovascular accident within 6 months

METHOD OF TREATMENT ASSIGNMENT Patients meeting the study criteria and providing informed
consent will be randomized according to the attached randomization chart (Appendix E) to
study or control arm until 10 eyes are assigned to each group. Patients with both eyes
eligible for the study will be assigned by coin flip.

STUDY TREATMENT Formulation Ranibizumab is formulated as a sterile solution aseptically
filled in a sterile, 2 mL or 3-mL stoppered glass vial. Each single use vial is designed to
deliver 0.05 mL of 10 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.

Further details and molecule characterization will be included in the Investigator Brochure.

Dosage, Administration, and Storage

1. Dosage Patients in the treatment and control arms will receive intravitreal injection
of 0.5 mg ranibizumab on the screening/Day 0 visit, and months 1 - 5. The need for
subsequent injections at months 6 - 11 will be determined by presence of persistent or
recurrent intraretinal fluid on OCT evaluation.

2. Administration

3. Storage Upon receipt, study drug kits should be refrigerated at 2C - 8C (36F - 46F).
DO NOT FREEZE. Do not use beyond the expiration date. Ranibizumab vials should remain
refrigerated. Protect vials from direct sunlight. 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.

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.

STUDY ASSESSMENTS Assessments during the Treatment Period Screening / Day 0 Visit
Informed consent Demographic data Medical and ocular history Vital signs (BP, heart
rate) Pregnancy test (if applicable) Best corrected visual acuity (BCVA) ETDRS chart
Slit lamp examination Intraocular pressure Dilated fundus examination Optical Coherence
Tomography UWFA Ranibizumab treatment + peripheral laser tx (Treatment group)
Ranibizumab treatment (Comparative group) SAE Monitoring Post-injection Phone Follow-up
Update medical and ocular history SAE Monitoring Months 1, 2, 3, 4, and 5 Visits Update
medical and ocular history Vital signs Best corrected visual acuity (BCVA) ETDRS chart
Slit lamp examination Intraocular pressure Dilated fundus examination UWFA (Month 3)
Ranibizumab treatment (Treatment and Comparative group) Optical Coherence Tomography
SAE monitoring Month 6 Visit Update medical and ocular history Vital signs Best
corrected visual acuity (BCVA) ETDRS chart Slit lamp examination Intraocular pressure
Dilated fundus examination Optical Coherence Tomography UWFA SAE monitoring Months 6,
7, 8, 9, 10, 11, and 12 Visits Update medical and ocular history Vital signs Best
corrected visual acuity (BCVA) ETDRS chart Slit lamp examination Intraocular pressure
Dilated fundus examination Optical Coherence Tomography Ranibizumab treatment if
necessary as determined by Optical Coherence Tomography assessment (Treatment and
Comparative group) SAE monitoring

Early Termination Assessments Subjects who withdraw from the study prior to completion
should return for an early termination evaluation 30 days (14 days) following the last
injection/study visit for monitoring of all adverse events (serious and nonserious).
The schedule of assessments for early termination is the same as that for the final
visit.

SUBJECT DISCONTINUATION Subjects have a right to withdraw from the study at any time.
The subject may be withdrawn from the study for any reasons: if it is in the best
interest of the subject, intercurrent illness, adverse events, or worsening condition.
The Western IRB may request the withdrawal of a subject because of protocol violations,
administrative reasons, or any other valid and ethical reasons.

If a subject discontinues from the study, he or she will not be allowed to re enter the
study.

Reasons for subject discontinuation may include, but are not limited to, the following:

Sensory rhegmatogenous retinal detachment or Stage 3 or 4 macular hole Investigator
determination that it is not in the best interest of the subject to continue
participation Pregnancy Verteporfin PDT treatment in the study eye Pegaptanib sodium
injection treatment in either eye Bevacizumab injection in either 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.

STUDY DISCONTINUATION

This study may be terminated by Western IRB or Retina Associates of Florida 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

STATISTICAL METHODS Analysis of the Conduct of the Study There is no formal sample size
calculation in this pilot study. As this is a phase I study, a sample size of 30
patients is chosen, making sure that it is feasible financially to conduct the study
and logistically to complete the study within 18 months. If and when the study is
planned for a phase II randomized control trial, appropriate statistical analysis will
be determined.

Safety Analyses Any adverse events, laboratory assessments, physical examinations,
vital signs, ocular examinations and measurements from all 30 subjects will be utilized
to summarize safety data for this pilot study.

Efficacy Analyses Primary Endpoint Mean change in 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 6. This will also include eyes with gain of
15 letters or more, or loss of 15 letters or more on the ETDRS eye chart Secondary
Endpoints Mean change in 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 2.

Percent reduction of foveal thickness by optical coherence tomography. Percent
reduction of macular volume by optical coherence tomography. Mean number of injections
between Months 6 and 12.

Missing Data Analyses of efficacy and safety will be based on available cases, without
imputation for missing values.

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.

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

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

- Disease related considerations:

- Study eye with macular edema secondary to branch retinal vein occlusion
characterized by:

- Fovea-involved macular edema of less than 12 months peripheral nonperfusion defined
as at least 5 disc areas of contiguous nonperfusion on ultra-widefield fluorescein
angiography absence of macular traction on clinical exam, UWFA, and OCT.

- Study eye with best corrected visual acuity between 20/40 (≤ 73 letters on ETDRS
chart) and 20/320 (≥ 19 letters on ETDRS chart)

- Other considerations

- Patient able to complete all study visits

Exclusion Criteria:

- Subjects who meet any of the following criteria will be excluded from this study:

- Pregnancy (positive pregnancy test) or lactation. Premenopausal women not using
adequate contraception. The following are considered effective means of
contraception: surgical sterilization or use of oral contraceptives, barrier
contraception with either a condom or diaphragm in conjunction with spermicidal
gel, an IUD, or contraceptive hormone implant or patch.

- Prior enrollment in the study

- 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

- Therapy with intravitreal triamcinolone, pegaptanib, ranibizumab, or bevacizumab
within the previous 3 months

- Previous macular or panretinal scatter laser photocoagulation

- Previous pars plana vitrectomy

- Visually-significant significant cataracts as primary reason for vision loss

- Myocardial infarction or cerebrovascular accident within 6 months